subject:(targeted sequencing)

Vanderbilt University

1. Hutchinson, Katherine Emily. Identification of Novel Targets for Therapy in Solid Tumors.

Degree: PhD, Cancer Biology, 2015, Vanderbilt University

► Solid tumor treatment paradigms have drastically improved in recent decades through direct targeting of the protein products of somatic, constitutively active “driver” mutations and their… (more)

▼ Solid tumor treatment paradigms have drastically improved in recent decades through direct targeting of the protein products of somatic, constitutively active “driver” mutations and their effector signaling pathways. Prior to these advances, metastatic solid tumors were primarily managed through administration of traditional cytotoxic chemotherapy. A prime example of this success is evident in melanomas expressing alterations at codon V600 of the serine-threonine kinase, BRAF. Compared to the chemotherapeutic standard-of-care in metastatic melanoma, dacarbazine, patients with BRAF V600E/K/M/R/D-mutated tumors exhibit significantly higher response and survival rates when treated with V600-variant specific small molecule inhibitors, vemurafenib and dabrafenib. However, potential driver mutations have not been identified for all tumors, and a large fraction of tumors are still “driver negative”. Herein, we sought to uncover new ‘drivers’ in pan-negative melanoma and pancreatic acinar cell carcinoma (PACC). While approximately 70% of melanomas harbor actionable driver alterations, the remaining one-third of patients are considered pan-negative. No driver alterations have yet been identified in patients with PACC, likely due to the rarity of this tumor type. Through whole-genome sequencing (WGS), we identified BRAF non-V600 alterations (L597, K601) in pan-negative melanomas that activate the mitogen-activation protein kinase (MAPK) signaling pathway and confer sensitivity to MEK1/2 inhibitors. Using comprehensive targeted, next-generation sequencing platforms, we identified MAPK-pathway activating RAF fusions in both pan-negative melanomas and PACCs. Finally, efforts to distinguish further pan-negative melanomas from one another revealed that a subset of pan-negative melanomas exhibit baseline activation of the ERBB family receptor tyrosine kinases (RTKs) EGFR, HER2 and HER3, suggesting a potential avenue for ERBB kinase inhibition in this disease. Collectively, this work describes the identification of novel and clinically actionable targets in previously un-druggable cancer subtypes. Advisors/Committee Members: Graham Carpenter (committee member), Jeffrey A. Sosman (committee member), Ann Richmond (committee member), William Pao (committee member), Jin Chen (Committee Chair).

Subjects/Keywords: next-generation sequencing; targeted therapy; cancer; melanoma

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APA (6^th Edition):

Hutchinson, K. E. (2015). Identification of Novel Targets for Therapy in Solid Tumors. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15255

Chicago Manual of Style (16^th Edition):

Hutchinson, Katherine Emily. “Identification of Novel Targets for Therapy in Solid Tumors.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed January 22, 2021. http://hdl.handle.net/1803/15255.

MLA Handbook (7^th Edition):

Hutchinson, Katherine Emily. “Identification of Novel Targets for Therapy in Solid Tumors.” 2015. Web. 22 Jan 2021.

Vancouver:

Hutchinson KE. Identification of Novel Targets for Therapy in Solid Tumors. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1803/15255.

Council of Science Editors:

Hutchinson KE. Identification of Novel Targets for Therapy in Solid Tumors. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/15255

Queensland University of Technology

2. Dutton-Regester, Ken. The identification of therapeutic targets in metastatic melanoma.

Degree: 2012, Queensland University of Technology

URL: https://eprints.qut.edu.au/53305/

► Metastatic melanoma, a cancer historically refractory to chemotherapeutic strategies, has a poor prognosis and accounts for the majority of skin cancer related mortality. Although the… (more)

▼ Metastatic melanoma, a cancer historically refractory to chemotherapeutic strategies, has a poor prognosis and accounts for the majority of skin cancer related mortality. Although the recent approval of two new drugs combating this disease, Ipilimumab and Vemurafenib (PLX4032), has demonstrated for the first time in decades an improvement in overall survival; the clinical efficacy of these drugs has been marred by severe adverse immune reactions and acquired drug resistance in patients, respectively. Thus, understanding the etiology of metastatic melanoma will contribute to the improvement of current therapeutic strategies while leading to the development of novel drug approaches. In order to identify recurrently mutated genes of therapeutic relevance in metastatic melanoma, a panel of stage III local lymph node melanomas were extensively characterised using high-throughput genomic technologies. This led to the identification of mutations in TFG in 5% of melanomas from a candidate gene sequencing approach using SNP array analysis, 24% of melanomas with mutations in MAP3K5 or MAP3K9 though unbiased whole-exome sequencing strategies, and inactivating mutations in NF1 in BRAF/NRAS wild type tumours though pathway analysis. Lastly, this thesis describes the development of a melanoma specific mutation panel that can rapidly identify clinically relevant mutation profiles that could guide effective treatment strategies through a personalised therapeutic approach. These findings are discussed in respect to a number of important issues raised by this study including the current limitation of next-generation sequencing technology, the difficulty in identifying ‘driver’ mutations critical to the development of melanoma due to high carcinogenic exposure by UV radiation, and the ultimate application of mutation screening in a personalised therapeutic setting. In summary, a number novel genes involved in metastatic melanoma have been identified that may have relevance for current therapeutic strategies in treating this disease.

Subjects/Keywords: melanomaration sequencing; somatic mutation; next-generation sequencing; targeted drug; cancer; ODTA

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APA (6^th Edition):

Dutton-Regester, K. (2012). The identification of therapeutic targets in metastatic melanoma. (Thesis). Queensland University of Technology. Retrieved from https://eprints.qut.edu.au/53305/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Dutton-Regester, Ken. “The identification of therapeutic targets in metastatic melanoma.” 2012. Thesis, Queensland University of Technology. Accessed January 22, 2021. https://eprints.qut.edu.au/53305/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Dutton-Regester, Ken. “The identification of therapeutic targets in metastatic melanoma.” 2012. Web. 22 Jan 2021.

Vancouver:

Dutton-Regester K. The identification of therapeutic targets in metastatic melanoma. [Internet] [Thesis]. Queensland University of Technology; 2012. [cited 2021 Jan 22]. Available from: https://eprints.qut.edu.au/53305/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Dutton-Regester K. The identification of therapeutic targets in metastatic melanoma. [Thesis]. Queensland University of Technology; 2012. Available from: https://eprints.qut.edu.au/53305/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto

3. Chow, Signy. Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease.

Degree: 2017, University of Toronto

URL: http://hdl.handle.net/1807/79321

►

Multiple Myeloma (MM) is an incurable plasma cell dyscrasia characterized by recurrent translocations into immunoglobulin loci and a unique V(D)J rearrangement signature that can be… (more)

Subjects/Keywords: Genomics; Immunoglobulin; Lymphoproliferative; Multiple Myeloma; Next Generation Sequencing; Targeted Capture Sequencing; 0564

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APA (6^th Edition):

Chow, S. (2017). Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/79321

Chicago Manual of Style (16^th Edition):

Chow, Signy. “Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease.” 2017. Masters Thesis, University of Toronto. Accessed January 22, 2021. http://hdl.handle.net/1807/79321.

MLA Handbook (7^th Edition):

Chow, Signy. “Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease.” 2017. Web. 22 Jan 2021.

Vancouver:

Chow S. Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1807/79321.

Council of Science Editors:

Chow S. Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Disease. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79321

University of New Mexico

4. Rawat, Priyanka. Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine.

Degree: Biomedical Engineering, 2017, University of New Mexico

URL: https://digitalrepository.unm.edu/bme_etds/16

► Astounding success of Human genome project and accelerating success of sequencing technologies have enabled $ 1000 genome goals possible. But, this is still far-fetched… (more)

Subjects/Keywords: Genotyping; affordable; dna sequencing; targeted sequencing; Biomedical Engineering and Bioengineering; Other Medicine and Health Sciences

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APA (6^th Edition):

Rawat, P. (2017). Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine. (Doctoral Dissertation). University of New Mexico. Retrieved from https://digitalrepository.unm.edu/bme_etds/16

Chicago Manual of Style (16^th Edition):

Rawat, Priyanka. “Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine.” 2017. Doctoral Dissertation, University of New Mexico. Accessed January 22, 2021. https://digitalrepository.unm.edu/bme_etds/16.

MLA Handbook (7^th Edition):

Rawat, Priyanka. “Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine.” 2017. Web. 22 Jan 2021.

Vancouver:

Rawat P. Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine. [Internet] [Doctoral dissertation]. University of New Mexico; 2017. [cited 2021 Jan 22]. Available from: https://digitalrepository.unm.edu/bme_etds/16.

Council of Science Editors:

Rawat P. Next generation sequencing technologies for real-time genotyping and targeted sequencing for precision medicine. [Doctoral Dissertation]. University of New Mexico; 2017. Available from: https://digitalrepository.unm.edu/bme_etds/16

Universiteit Utrecht

5. Nicolaou, N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.

Degree: 2016, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/328921

► This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition… (more)

▼ This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition drives the development of congenital anomalies of the kidney and urinary tract, but the clinical variability and large genetic heterogeneity requires a sophisticated approach to detect the genetic causes. In this thesis we sequenced 208 genes suspected to be involved in CAKUT in 453 patients with CAKUT, in order to detect genetic variants that are likely to disrupt gene function and lead to CAKUT. We identified multiple rare genetic variants that are predicted to disrupt the function of their corresponding gene. However, the results of a statistical analysis suggest that rare genetic variants in these tested genes are not more frequent in patients in comparison to healthy individuals. This suggests that none of these genes plays a major role in the development of CAKUT. It could be that variants in other genes may have a bigger effect on the risk of developing CAKUT, or that the risk of CAKUT depends on a combination of multiple genetic factors with a small effect and a number of environmental factors. Therefore, future investigations should test the role of all genes in CAKUT as well as environmental factors using even more patients with CAKUT. We also present two individual patients with a unique combination of symptoms that has not been reported in the literature before. We describe the first application of whole genome sequencing in a patient with kidney disease to identify the genetic cause, which resulted in the identification of variants in multiple genes that are functionally related to the phenotypes observed in the patient. In another patient we identified and characterized a single genetic mutation that completely stops the expression of an essential protein in the kidney and lung tissue. The mutation leads to a new multi-organ disorder observed in our patient, including interstitial lung disease and congenital nephrotic syndrome. This discovery enabled the use of genetic testing in our hospital for other newborns with similar symptoms, thereby facilitating an early diagnosis and enabling the risk estimation of having more affected offspring. Further, we discuss the tools that are available to scientists today to unravel the function of newly identified genes and study the alterations in gene function that may be caused by such uncharacterized genetic variants. We performed functional characterization tests to elucidate the impact of the variants in a single gene detected in several CAKUT patients. Here, we provide experimental evidence suggesting that the variants exert disruptive effects on, at least, one of the functions of the gene. Our results open a big question about the possibility of microscopic, hair-like structures on eukaryotic cells, called cilia, having an effect on the development of CAKUT. Advisors/Committee Members: Knoers, N.V.A.M., Giles, R.H., Renkema, K.Y..

Subjects/Keywords: CAKUT; NGS; cilia; kidney development; targeted sequencing; nephrotic syndrome; WGS

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APA (6^th Edition):

Nicolaou, N. (2016). Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/328921

Chicago Manual of Style (16^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Doctoral Dissertation, Universiteit Utrecht. Accessed January 22, 2021. http://dspace.library.uu.nl:8080/handle/1874/328921.

MLA Handbook (7^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Web. 22 Jan 2021.

Vancouver:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2016. [cited 2021 Jan 22]. Available from: http://dspace.library.uu.nl:8080/handle/1874/328921.

Council of Science Editors:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Doctoral Dissertation]. Universiteit Utrecht; 2016. Available from: http://dspace.library.uu.nl:8080/handle/1874/328921

Vanderbilt University

6. Song, Zhuo. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.

Degree: PhD, Human Genetics, 2012, Vanderbilt University

URL: http://hdl.handle.net/1803/10702

► The activity of polymerase ã (pol ã) is complicated. To understand how its kinetics values affect the final function of the pol ã, I created… (more)

Subjects/Keywords: tumor somatic mutations; targeted sequencing; NRTI; polymerase gamma; mtDNA replication

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APA (6^th Edition):

Song, Z. (2012). Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10702

Chicago Manual of Style (16^th Edition):

Song, Zhuo. “Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 22, 2021. http://hdl.handle.net/1803/10702.

MLA Handbook (7^th Edition):

Song, Zhuo. “Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.” 2012. Web. 22 Jan 2021.

Vancouver:

Song Z. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1803/10702.

Council of Science Editors:

Song Z. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/10702

7. Hathaway, Nicholas J. A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures.

Degree: Department of Bioinformatics and Integrative Biology, 2018, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/970

► The rapid development of DNA sequencing technologies has opened up new avenues of research, including the investigation of population structure within infectious diseases (both… (more)

Subjects/Keywords: plasmodium; sequencing; infectious diseases; targeted amplicon; Bioinformatics; Computational Biology; Parasitic Diseases

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APA (6^th Edition):

Hathaway, N. J. (2018). A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/970

Chicago Manual of Style (16^th Edition):

Hathaway, Nicholas J. “A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures.” 2018. Doctoral Dissertation, U of Massachusetts : Med. Accessed January 22, 2021. https://escholarship.umassmed.edu/gsbs_diss/970.

MLA Handbook (7^th Edition):

Hathaway, Nicholas J. “A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures.” 2018. Web. 22 Jan 2021.

Vancouver:

Hathaway NJ. A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2018. [cited 2021 Jan 22]. Available from: https://escholarship.umassmed.edu/gsbs_diss/970.

Council of Science Editors:

Hathaway NJ. A suite of computational tools to interrogate sequence data with local haplotype analysis within complex Plasmodium infections and other microbial mixtures. [Doctoral Dissertation]. U of Massachusetts : Med; 2018. Available from: https://escholarship.umassmed.edu/gsbs_diss/970

University of Melbourne

8. Kondrashova, Olga. Molecular profiling of ovarian cancer to guide targeted treatment.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/58897

► Ovarian cancer is a complex disease composed of multiple distinct molecular and clinical subtypes. The survival rate for ovarian cancer has remained largely unchanged over… (more)

▼ Ovarian cancer is a complex disease composed of multiple distinct molecular and clinical subtypes. The survival rate for ovarian cancer has remained largely unchanged over the past three decades, despite the rapid advancement of the knowledge of the molecular and genetic mechanisms underlying most of the subtypes of ovarian cancer. There is, therefore, an urgent need to rapidly translate this knowledge into improved clinical outcomes for patients with ovarian cancer. There have been significant clinical responses of certain types of cancer to targeted therapies that are designed to inhibit specific molecular defects that some tumours appear to be dependent upon. To assist in allocating patients with ovarian cancer to targeted therapies, two customised assays for mutation and copy number alteration detection were developed for molecular profiling. A panel of 29 genes, which are commonly mutated in ovarian cancer, and are potentially therapeutically targeted, was selected to be screened using an amplicon-based assay, designed for next generation sequencing. Seventy six ovarian cancer cases with matched formalin-fixed paraffin- embedded tumour tissue, snap-frozen tumour tissue and blood samples were used for the assay validation and estimation of the diagnostic yield. A panel of 11 commonly copy number altered genes in ovarian cancer was also selected for screening with a herein developed method for multiplex low-level copy number detection. Furthermore, a thorough assessment and optimisation of the available and developed analysis methods was performed to ensure accurate analysis and reporting of mutations and copy number alterations. Thirty five patients with advanced ovarian cancer were tested using the developed assays as part of the ALLOCATE study, with genetic changes detected in 90.9%, demonstrating a high diagnostic yield. Molecular profiling of these cases was not only useful in identification of possible targeted treatment strategies with the aim of improving clinical outcomes, but also assisted in determining the correct diagnosis. Moreover, a novel algorithm was proposed for the prediction of individual tumour response to PARP inhibitors, a promising targeted treatment in high-grade serous ovarian cancer.

Subjects/Keywords: ovarian cancer; cancer; personalised medicine; next-generation sequencing; targeted treatments

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APA (6^th Edition):

Kondrashova, O. (2015). Molecular profiling of ovarian cancer to guide targeted treatment. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/58897

Chicago Manual of Style (16^th Edition):

Kondrashova, Olga. “Molecular profiling of ovarian cancer to guide targeted treatment.” 2015. Doctoral Dissertation, University of Melbourne. Accessed January 22, 2021. http://hdl.handle.net/11343/58897.

MLA Handbook (7^th Edition):

Kondrashova, Olga. “Molecular profiling of ovarian cancer to guide targeted treatment.” 2015. Web. 22 Jan 2021.

Vancouver:

Kondrashova O. Molecular profiling of ovarian cancer to guide targeted treatment. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11343/58897.

Council of Science Editors:

Kondrashova O. Molecular profiling of ovarian cancer to guide targeted treatment. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/58897

Virginia Commonwealth University

9. Loken, Erik. Identifying functional variation in schizophrenia GWAS loci by pooled sequencing.

Degree: PhD, Clinical and Translational Sciences, 2014, Virginia Commonwealth University

URL: https://doi.org/10.25772/QXEJ-QC63 ; https://scholarscompass.vcu.edu/etd/3515

► Schizophrenia demonstrates high heritability in part accounted for by common simple nucleotide variants (SNV), rare copy number variants (CNV) and, most recently, rare SNVs… (more)

▼ Schizophrenia demonstrates high heritability in part accounted for by common simple nucleotide variants (SNV), rare copy number variants (CNV) and, most recently, rare SNVs Although heritability explained by rare SNVs and CNVs is small compared to that explained by common SNVs, rare SNVs in functional sequences may identify specific disease mechanisms. However, current exome methods do not capture a large proportion of potentially functional bases where rare variation may impact disease risk: as much as two-thirds of conserved sequences lie outside the exome in non-coding regions of cross-species evolutionary constraint. We reasoned that the candidate loci from the Psychiatric Genomics Consortium Phase 1 (PGC-1) schizophrenia study represent good target loci to test for the impact of rare SNVs in non-coding constrained regions. We developed custom reagents to capture mammalian constrained non-coding regions, exons, and 5’- and 3’-untranslated regions (UTRs) in the 12 PGC-1 loci for pooled sequencing in 912 cases and 936 controls. Compared to our coding targets, our noncoding targets contain substantially more highly conserved bases (46,412 vs. 31,609) and variants (390 vs. 193). Using C-alpha to detect excess variance due to aggregate risk increasing or decreasing rare SNV effects, we identified signals attributable to alleles with MAF < 0.1% in both coding sequences and in functional non-coding sequences, including variants within ENCODE transcription factor binding sites, DNase hypersensitive regions, and histone modification sites in neuronal cell lines. We also observed significant excess risk-altering variation in the CUB domain of CSMD1, a gene expressed in the developing central nervous system. These results support the hypothesis that common and rare variants in the same loci contribute to schizophrenia risk, but highlight the need to expand capture strategies in order to detect trait-relevant sequence variation in a broader set of functional sequences. Advisors/Committee Members: Brien Riley.

Subjects/Keywords: schizophrenia; genetics; schizophrenia genetics; psychiatric genetics; rare variation; common variation; sequencing; pooled sequencing; targeted sequencing; Psychiatry and Psychology

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APA (6^th Edition):

Loken, E. (2014). Identifying functional variation in schizophrenia GWAS loci by pooled sequencing. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/QXEJ-QC63 ; https://scholarscompass.vcu.edu/etd/3515

Chicago Manual of Style (16^th Edition):

Loken, Erik. “Identifying functional variation in schizophrenia GWAS loci by pooled sequencing.” 2014. Doctoral Dissertation, Virginia Commonwealth University. Accessed January 22, 2021. https://doi.org/10.25772/QXEJ-QC63 ; https://scholarscompass.vcu.edu/etd/3515.

MLA Handbook (7^th Edition):

Loken, Erik. “Identifying functional variation in schizophrenia GWAS loci by pooled sequencing.” 2014. Web. 22 Jan 2021.

Vancouver:

Loken E. Identifying functional variation in schizophrenia GWAS loci by pooled sequencing. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2014. [cited 2021 Jan 22]. Available from: https://doi.org/10.25772/QXEJ-QC63 ; https://scholarscompass.vcu.edu/etd/3515.

Council of Science Editors:

Loken E. Identifying functional variation in schizophrenia GWAS loci by pooled sequencing. [Doctoral Dissertation]. Virginia Commonwealth University; 2014. Available from: https://doi.org/10.25772/QXEJ-QC63 ; https://scholarscompass.vcu.edu/etd/3515

University of Melbourne

10. Mountford, Hayley S. Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/93558

► Inherited defects in mitochondrial oxidative phosphorylation (OXPHOS) are the most common inborn error of metabolism, affecting at least 1 in 5000 live births (Skladal, Halliday… (more)

▼ Inherited defects in mitochondrial oxidative phosphorylation (OXPHOS) are the most common inborn error of metabolism, affecting at least 1 in 5000 live births (Skladal, Halliday et al. 2003), and predominantly affect organs with high-energy consumption such as the brain, skeletal muscle, cardiac muscle and liver. Mitochondrial diseases are notoriously difficult to diagnose, as they show extreme clinical heterogeneity, presenting at any age and with any level of severity, and typically impact on multiple organ systems (Munnich and Rustin 2001). They are also genetically heterogeneous with over 200 mitochondrial DNA and nuclear DNA encoding genes associated with OXPHOS disease. Despite the large number of disease genes being identified, many patients with OXPHOS disease remain without a molecular diagnosis. We developed a targeted DNA capture and massively parallel sequencing method to detect variants within 1,034 genes encoding proteins known or implicated as having a mitochondrial function, known as the MitoExome. My PhD studies have focused on the characterisation of two novel genes identified by MitoExome sequencing; UQCC2 and UQCR10. Both UQCC2 and UQCR10 are components of mitochondrial complex III. By using a panel of patients with causative mutations in a range of different complex III subunits and assembly factors, we have further characterised the assembly pathway of complex III. Of the 45 patients who underwent MitoExome sequencing, a third remain without a molecular cause identified. To address this, I utilised several alternative analysis strategies to pursue molecular diagnoses in patients where a causative mutation had not been easily identified. Reanalysis of the MitoExome data using two different analysis pipelines (Cpipe and xBrowse) identified an additional patient diagnosis in RMND1. Comparison between the two pipelines highlighted some key differences between analyses for research compared to a clinical setting. The Birth Prevalence cohort is a 12 year follow up study to revisit the original cohort reported by Skladal and colleagues in 2003 (Skladal, Halliday et al. 2003). This study identified 86 patients with a confirmed diagnosis of mitochondrial disease who were born in South Eastern Australia between 1987 and 1996. This cohort was used to calculate the birth prevalence of mitochondrial disorders as 1 in 5000 live births. At the time of publication 23% (n=20/86) of patients had a molecular diagnosis identified. The 2015 review of this cohort found an additional 19 patients who fit the inclusion criteria, bringing the total number of patients to 105. Currently, 70% (n=73/105) of Birth Prevalence cohort patients have a molecular cause identified. This PhD describes some preliminary molecular investigation of 19 patients, who are as yet without a molecular diagnosis.

Subjects/Keywords: mitochondrial deficiency; mitochondrial disease; genetics; human genetics; complex III; next generation sequencing; massively parallel sequencing; disease genetics; candidate gene sequencing; birth prevalence estimate; OXPHOS; oxidative phosphorylation; MitoExome; targeted sequencing

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APA (6^th Edition):

Mountford, H. S. (2015). Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/93558

Chicago Manual of Style (16^th Edition):

Mountford, Hayley S. “Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach.” 2015. Doctoral Dissertation, University of Melbourne. Accessed January 22, 2021. http://hdl.handle.net/11343/93558.

MLA Handbook (7^th Edition):

Mountford, Hayley S. “Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach.” 2015. Web. 22 Jan 2021.

Vancouver:

Mountford HS. Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11343/93558.

Council of Science Editors:

Mountford HS. Using massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/93558

University of Iowa

11. Shearer, Aiden Eliot. Deafness in the genomics era.

Degree: PhD, Molecular Physiology and Biophysics, 2014, University of Iowa

URL: https://ir.uiowa.edu/etd/4750

► Deafness is the most common sensory deficit in humans, affecting 278 million people worldwide. Non-syndromic hearing loss (NSHL), hearing loss not associated with other… (more)

▼ Deafness is the most common sensory deficit in humans, affecting 278 million people worldwide. Non-syndromic hearing loss (NSHL), hearing loss not associated with other symptoms, is the most common type of hearing loss and most NSHL in developed countries is due to a genetic cause. The inner ear is a remarkably complex organ, and as such, there are estimated to be hundreds of genes with mutations that can cause hearing loss. To date, 62 of these genes have been identified. This extreme genetic heterogeneity has made comprehensive genetic testing for deafness all but impossible due to low-throughput genetic testing methods that sequence a single gene at a time. The human genome project was completed in 2003. Soon after, genomic technologies, including massively parallel sequencing, were developed. MPS gives the ability to sequence millions or billions of DNA base-pairs of the genome simultaneously. The goal of my thesis work was to use these newly developed genomic technologies to create a comprehensive genetic testing platform for deafness and use this platform to answer key scientific questions about genetic deafness. This platform would need to be relatively inexpensive, highly sensitive, and accurate enough for clinical diagnostics. In order to accomplish this goal we first determined the best methods to use for this platform by comparing available methods for isolation of all exons of all genes implicated in deafness and massively parallel sequencers. We performed this pilot study on a limited number of patient samples, but were able to determine that solution-phase targeted genomic enrichment (TGE) and Illumina sequencing presented the best combination of sensitivity and cost. We decided to call this platform and diagnostic pipeline OtoSCOPE®. Also during this study we identified several weaknesses with the standard method for TGE that we sought to improve. The next aim was to focus on these weaknesses to develop an improved protocol for TGE that was highly reproducible and efficient. We developed a new protocol and tested the limits of sequencer capacity. These findings allowed us to translate OtoSCOPE® to the clinical setting and use it to perform comprehensive genetic testing on a large number of individuals in research studies. Finally, we used the OtoSCOPE® platform to answer crucial questions about genetic deafness that had remained unanswered due to the low-throughput genetic testing methods available previously. By screening 1,000 normal hearing individuals from 6 populations we determined the carrier frequency for non-DFNB1 recessive deafness-causing mutations to be 3.3%. Our findings will also help us to interpret variants uncovered during analysis of deafness genes in affected individuals. When we used OtoSCOPE® to screen 100 individuals with apparent genetic deafness, we were able to provide a genetic diagnosis in 45%, a large increase compared to previous gene-by-gene sequencing methods. Because it provides a pinpointed etiological diagnosis, genetic… Advisors/Committee Members: Smith, Richard J. H. (supervisor).

Subjects/Keywords: Deafness; Genomics; Hearing loss; Massively parallel sequencing; Targeted genomic enrichment; Usher syndrome; Biophysics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Shearer, A. E. (2014). Deafness in the genomics era. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/4750

Chicago Manual of Style (16^th Edition):

Shearer, Aiden Eliot. “Deafness in the genomics era.” 2014. Doctoral Dissertation, University of Iowa. Accessed January 22, 2021. https://ir.uiowa.edu/etd/4750.

MLA Handbook (7^th Edition):

Shearer, Aiden Eliot. “Deafness in the genomics era.” 2014. Web. 22 Jan 2021.

Vancouver:

Shearer AE. Deafness in the genomics era. [Internet] [Doctoral dissertation]. University of Iowa; 2014. [cited 2021 Jan 22]. Available from: https://ir.uiowa.edu/etd/4750.

Council of Science Editors:

Shearer AE. Deafness in the genomics era. [Doctoral Dissertation]. University of Iowa; 2014. Available from: https://ir.uiowa.edu/etd/4750

University of Melbourne

12. Brown, Lauren Maree. Mechanisms of signal transduction and treatment implications in childhood leukaemia.

Degree: 2019, University of Melbourne

URL: http://hdl.handle.net/11343/233667

► Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric malignancy and while the prognosis for patients has dramatically improved, specific molecular subtypes are… (more)

▼ Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric malignancy and while the prognosis for patients has dramatically improved, specific molecular subtypes are still associated with inferior outcomes. Comprehensive sequencing studies of large cohorts have identified an expanding number of recurrent drivers associated with B-cell ALL (B-ALL), notably gene fusions, and has resulted in the characterisation of 23 subtypes. Associated risk of relapse has been established for many of these molecular subtypes and is incorporated into clinical risk stratification algorithms. However, molecular features of T-cell ALL (T-ALL) are yet to be incorporated into these algorithms. For a subset of B-ALL patients and the majority of T-ALL patients there is a great need to expand of molecular diagnostic testing to identify recurrent molecular features or potentially actionable lesions. In this thesis, we aimed to identify novel and rare fusion genes in paediatric ALL using RNA sequencing (RNA-seq) and understand the mechanisms by which these fusions function to drive leukaemia. We performed RNA-seq on 126 ALL patients diagnosed at the Royal Children’s Hospital (RCH) to test the utility of implementing RNA-seq into standard of care diagnostic pipelines. We showed that RNA-seq reliably detected gene fusions identified by clinical diagnostics but has limitation to detect gene fusions in samples with low tumour burden, lowly expressed fusion transcripts (KMT2A rearrangements), and rearrangements involving promotor or enhancer regions (IGH rearrangements). We additionally developed analysis tools to identify IKZF1 deletions and a gene expression classifier to predict Ph-like, ETV6-RUNX1+, and ERG-deleted/DUX4 rearranged ALL, and showed that we could use RNA-seq data to molecularly classify patients that did not express standard lesions. This chapter of the thesis is accompanied by supporting material contained in "Supplementary_table_1.xlsx", which details transcript information for fusion genes identified by the fusion-finding algorithm, JAFFA, in this patient cohort. Using RNA-seq data, we identified a number of rare and novel tyrosine-kinase activating fusion genes, which are potentially therapeutically targetable with tyrosine kinase inhibitors (TKIs). We cloned and validated the transforming capacity of these fusions in cytokine-dependent cell lines and tested response to therapies. These included a rare CNTRL-FGFR1 fusion that we identified in two patients with biphenotypic leukaemia, and two rare ABL1 fusions, SFPQ-ABL1 and SNX2-ABL1, identified in two patients with B-ALL. We showed that the structure of the CNTRL-FGFR1 fusion differed from what was previously described, and that the fusion is transcribed from exon one of CNTRL and undergoes alternative splicing. We confirmed that cells expressing the full-length form of CNTRL-FGFR1 were sensitive to TKIs that targeted FGFR1, notably ponatinib. In addition, we designed a Droplet Digital PCR (ddPCR) assay that detects CNTRL-FGFR1, using transcript-specific…

Subjects/Keywords: acute lymphoblastic leukaemia; RNA sequencing; fusion genes; tyrosine kinases; signal transduction; targeted therapies

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Brown, L. M. (2019). Mechanisms of signal transduction and treatment implications in childhood leukaemia. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/233667

Chicago Manual of Style (16^th Edition):

Brown, Lauren Maree. “Mechanisms of signal transduction and treatment implications in childhood leukaemia.” 2019. Doctoral Dissertation, University of Melbourne. Accessed January 22, 2021. http://hdl.handle.net/11343/233667.

MLA Handbook (7^th Edition):

Brown, Lauren Maree. “Mechanisms of signal transduction and treatment implications in childhood leukaemia.” 2019. Web. 22 Jan 2021.

Vancouver:

Brown LM. Mechanisms of signal transduction and treatment implications in childhood leukaemia. [Internet] [Doctoral dissertation]. University of Melbourne; 2019. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11343/233667.

Council of Science Editors:

Brown LM. Mechanisms of signal transduction and treatment implications in childhood leukaemia. [Doctoral Dissertation]. University of Melbourne; 2019. Available from: http://hdl.handle.net/11343/233667

13. Daniel Lôpo Polla. Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas.

Degree: 2013, Universidade Católica de Brasilia

URL: http://www.bdtd.ucb.br/tede/tde_busca/arquivo.php?codArquivo=2093

►

As displasias esqueléticas compreendem um grande grupo de mais de 450 doenças clinicamente distintas e geneticamente heterogêneas associadas a mutações em mais de 300 genes.… (more)

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As displasias esqueléticas compreendem um grande grupo de mais de 450 doenças clinicamente distintas e geneticamente heterogêneas associadas a mutações em mais de 300 genes. Avaliações clínicas e achados radiológicos são utilizados para o diagnóstico dessas doenças. No entanto, devido à heterogeneidade genética dos fenótipos, seu diagnóstico definitivo é complexo. Com o desenvolvimento de técnicas moleculares e a elucidação das bases moleculares dessas doenças, os testes moleculares se tornaram úteis no auxílio do diagnóstico dessas displasias. Uma vez que diversos genes têm sido associados a estas doenças, abordagens padrão para seu diagnóstico molecular, utilizando o sequenciamento de Sanger, podem ser demoradas e ter um alto custo. Para superar essas limitações, foi utilizado o sequenciamento de exoma parcial e construído um painel de 1,4Mb para a captura de todos os éxons de 309 genes envolvidos em displasias esqueléticas, além de 28 regiões genômicas que sofrem deleções associadas com essas doenças. O objetivo principal foi o de fornecer uma ferramenta que possa analisar simultaneamente e com alta confiança todos os genes conhecidos relacionados às displasias esqueléticas, produzindo dados que possam ser cruzados com informações clínicas para chegar a um diagnóstico definitivo. Amostras de DNA de 93 indivíduos, com diagnóstico clínico prévio de displasia esquelética, foram sequenciados multiplexados em oito corridas usando a plataforma de sequenciamento de DNA Illumina MiSeq. A reprodutibilidade da metodologia foi testada repetindo todo o processo em três amostras. O sequenciamento de alto desempenho dos éxons capturados resultou em uma cobertura média de 140X. Mutações causais foram caracterizadas em 15 pacientes até o momento, incluindo 7 mutações não reportadas anteriormente. A confirmação de 9 mutações foi realizada por meio do sequenciamento de Sanger e todas foram confirmadas. O painel de genes construído nesse trabalho fornece uma ferramenta de diagnóstico molecular rápida, precisa e de baixo custo e pode auxiliar no diagnóstico definitivo de doenças esqueléticas.

Skeletal dysplasias comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Clinical and radiological findings are used to diagnose these diseases. However, due to the genetic heterogeneity of these disorders, the diagnostic process is complex. With advances in molecular genetics and the elucidation of the molecular basis of many of these diseases, molecular tests have become useful in the diagnosis of skeletal dysplasias. Since many different genes have been associated with these disorders, standard diagnostic approaches using Sanger sequencing can be expensive and time consuming. To overcome these limitations, we used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4800 exons in 309 genes involved in skeletal dysplasias, as well as 28 genomic regions which when deleted are associated with these diseases.…

Advisors/Committee Members: Rinaldo Wellerson Pereira, Robert Edward Pogue.

Subjects/Keywords: genomas; biotecnologia; diagnóstico molecular; displasia esquelética; GENETICA; molecular diagnosis; skeletal dysplasias; ngs; targeted sequencing; exome; GENETICA

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APA (6^th Edition):

Polla, D. L. (2013). Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas. (Masters Thesis). Universidade Católica de Brasilia. Retrieved from http://www.bdtd.ucb.br/tede/tde_busca/arquivo.php?codArquivo=2093

Chicago Manual of Style (16^th Edition):

Polla, Daniel Lôpo. “Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas.” 2013. Masters Thesis, Universidade Católica de Brasilia. Accessed January 22, 2021. http://www.bdtd.ucb.br/tede/tde_busca/arquivo.php?codArquivo=2093.

MLA Handbook (7^th Edition):

Polla, Daniel Lôpo. “Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas.” 2013. Web. 22 Jan 2021.

Vancouver:

Polla DL. Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas. [Internet] [Masters thesis]. Universidade Católica de Brasilia; 2013. [cited 2021 Jan 22]. Available from: http://www.bdtd.ucb.br/tede/tde_busca/arquivo.php?codArquivo=2093.

Council of Science Editors:

Polla DL. Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas. [Masters Thesis]. Universidade Católica de Brasilia; 2013. Available from: http://www.bdtd.ucb.br/tede/tde_busca/arquivo.php?codArquivo=2093

McMaster University

14. Enk, Jacob M. Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits.

Degree: PhD, 2014, McMaster University

URL: http://hdl.handle.net/11375/14108

►

Mammoths (Mammuthus) have been studied extensively at the genetic level. However due to both taphonomic and technological limitations, only one of several late Pleistocene… (more)

Subjects/Keywords: Mammoths; ancient DNA; high-throughput sequencing; targeted enrichment; Biological and Physical Anthropology; Biology; Biological and Physical Anthropology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Enk, J. M. (2014). Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/14108

Chicago Manual of Style (16^th Edition):

Enk, Jacob M. “Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits.” 2014. Doctoral Dissertation, McMaster University. Accessed January 22, 2021. http://hdl.handle.net/11375/14108.

MLA Handbook (7^th Edition):

Enk, Jacob M. “Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits.” 2014. Web. 22 Jan 2021.

Vancouver:

Enk JM. Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits. [Internet] [Doctoral dissertation]. McMaster University; 2014. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11375/14108.

Council of Science Editors:

Enk JM. Mammoth phylogeography south of the ice: large-scale sequencing of degraded DNA from temperate deposits. [Doctoral Dissertation]. McMaster University; 2014. Available from: http://hdl.handle.net/11375/14108

15. Héritier, Sébastien. Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis.

Degree: Docteur es, Sciences de la vie et de la santé, 2017, Université Paris-Saclay (ComUE)

URL: http://www.theses.fr/2017SACLS002

►

L’histiocytose langerhansienne (HL) est la plus fréquente des histiocytoses, liée à l’accumulation de cellules pathologiques de phénotype langerhansien. La découverte de la mutation somatique BRAFV600E… (more)

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L’histiocytose langerhansienne (HL) est la plus fréquente des histiocytoses, liée à l’accumulation de cellules pathologiques de phénotype langerhansien. La découverte de la mutation somatique BRAFV600E dans environ 50% des cas à ouvert un nouveau champ d’investigation pour tirer bénéfice de ce statut moléculaire pour la prise en charge des patients.Tout d’abord, nous avons montré l’efficacité des inhibiteurs de BRAF sans rapporter de résistance dans les formes actives d’HL, en particulier dans les formes multisystémiques avec atteinte des organes à risque (MS OR+) du nourrissons, confirmant le rôle driver de cette mutation dans l’HL. Toutefois, après l’arrêt du traitement administré durant 2 à 6 mois, de nombreuses récidives ont été constatées.Ensuite, nous avons montré que pour les enfants atteints d’HL, la mutation BRAFV600E était significativement associée aux formes MS OR+, retrouvée dans 87,8% de ces cas. Comparés aux patients non mutés BRAF, les patients avec la mutation BRAFV600E présentaient un taux de résistance plus élevé à la chimiothérapie de première ligne velbé - corticoïde (21,9% contre 3,3%), un taux plus élevé de réactivation à 5 ans (42,8% contre 28,1%) et un taux de séquelles supérieur (27,9% contre 12,6%).Par ailleurs, nous avons montré que, pour les HL BRAFV600E mutées, la quantification de BRAFV600E dans l’ADN libre circulant par PCR digitale en gouttelette était un biomarqueur pertinent pour les cas d’HL MS OR+ et les présentations résistantes au traitement de première ligne.Enfin, après un criblage de points chauds mutationnels d’une série d’échantillons tissulaires d’HL ayant permis de mettre en évidence un cas avec la mutation somatique PIK3CAE542K, 9 couples d’échantillons tumeur/constitutionnel ont été étudiés par séquençage d’exome. Cela nous a permis de mettre en évidence une mutation récurrente (n=2) de BRAF au niveau du site d’épissage 5’ (donneur) de l’intron 12. Selon l’analyse de l’ARN, cette mutation conduirait à l’insertion de 3 acides aminés (LLR) dans le domaine kinase de la protéine mutée, dont l’analyse fonctionnelle est en cours.

Langerhans cell histiocytosis (LCH) is the most common type of histiocytosis owing to accumulation of pathologic CD1a+ CD207+ histiocytes. The identification of BRAFV600E in more than half of patients with LCH has launched a new field of investigation to study potential patient’s management benefits and implications from this molecular status.First, in BRAFV600E mutated LCH, we reported the effectiveness of BRAF inhibitors. Efficacy with no resistance to vemurafenib was reported in all cases with active LCH disease, especially for multi-system LCH with risk organ (MS RO+) involvement, confirming the driver status of this mutation in LCH. However, after discontinuation of this treatment administered during 2-6 months, many recurrences were observed.Then, we showed that children with BRAFV600E mutated LCH manifested more severe disease, comprised 87.8% of patients with MS RO+ involvement. Compared to patients with wild-type BRAF, patients with…

Advisors/Committee Members: Émile, Jean-François (thesis director).

Subjects/Keywords: Histiocytose langerhansienne; Brafv600e; Thérapie ciblée; Biomarqueurs; Séquençage d’exome; Langerhans cell histiocytosis; Brafv600e; Targeted therapy; Biomarkers; Whole exome sequencing

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Héritier, S. (2017). Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2017SACLS002

Chicago Manual of Style (16^th Edition):

Héritier, Sébastien. “Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis.” 2017. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed January 22, 2021. http://www.theses.fr/2017SACLS002.

MLA Handbook (7^th Edition):

Héritier, Sébastien. “Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis.” 2017. Web. 22 Jan 2021.

Vancouver:

Héritier S. Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2017. [cited 2021 Jan 22]. Available from: http://www.theses.fr/2017SACLS002.

Council of Science Editors:

Héritier S. Bases moléculaires de l’histiocytose langerhansienne : Molecular Basis of Langerhans Cell Histiocytosis. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2017. Available from: http://www.theses.fr/2017SACLS002

Texas Medical Center

16. Reuther, Jacquelyn. INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU.

Degree: PhD, 2015, Texas Medical Center

URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/577

► Ductal carcinoma in situ (DCIS) is thought to be one of the earliest pre-invasive form of and non-obligate precursor to invasive ductal carcinoma (IDC).… (more)

▼ Ductal carcinoma in situ (DCIS) is thought to be one of the earliest pre-invasive form of and non-obligate precursor to invasive ductal carcinoma (IDC). There is an urgent need to identify predictive and prognostic biomarkers for breast cancers with a heightened risk of progression from DCIS to IDC. Our laboratory has previously discovered a novel TRIM family member, DEAR1 (Ductal Epithelium Associated Ring Chromosome 1, annotated as TRIM62) within chromosome 1p35.1, that is mutated and homozygously deleted in breast cancer and whose expression is downregulated/lost in DCIS. Previous work has shown that DEAR1 is a novel tumor suppressor that acts as a dominant regulator of polarity, tissue architecture, and TGFβ-driven epithelial-mesenchymal transition (EMT)¹^,². Herein, I have shown by pan-cancer database analysis that chromosomal loss of DEAR1 is a moderately frequent event in multiple epithelial cancers and that targeted deletion of Dear1 in the mouse recapitulates the tumor spectrum of human tumor types undergoing DEAR1 copy number losses, including mammary tumors. Therefore, these results indicate the relevance of the Dear1 mouse model to human disease and suggest that genomic alteration of DEAR1 could play a role in the etiology of multiple cancers, including breast cancer. Because DEAR1 is downregulated in DCIS and regulates polarity and EMT, I hypothesized that DEAR1 mutations might be driver events in the progression of DCIS to IDC. Therefore, targeted ultra-deep sequencing of DEAR1 was completed in FFPE samples of 17 Pure DCIS and 17 DCIS samples associated with invasive lesions. Deep sequencing of DCIS indicate DEAR1 is mutated in 71% of DCIS. Within these samples, multiple mutations within DEAR1, including exonic variants previously discovered in IDC and novel nonsense mutations were discovered and validated. Interestingly, variants in samples of DCIS associated with an invasive component indicate few variants shared between the two components, possibly supporting an independent yet parallel evolution between DCIS and IDC. Further, functional screens were performed on a subset of mutations identified and demonstrated that mutations effect DEAR1’s regulation of tissue architecture and TGFβ signaling. Altogether, this data suggests that genomic alteration of DEAR1 is an important mechanism for its loss of function and may be of significance for future targeted therapies aimed at the pathways regulated by DEAR1. Advisors/Committee Members: Dr. Ann Killary, Dr. Timothy McDonald, Dr. Subrata Sen.

Subjects/Keywords: ultra-deep targeted sequencing; DEAR1; TRIM62; DCIS; Invasive breast cancer; Computational Biology; Genetics; Genomics; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Reuther, J. (2015). INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/577

Chicago Manual of Style (16^th Edition):

Reuther, Jacquelyn. “INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU.” 2015. Doctoral Dissertation, Texas Medical Center. Accessed January 22, 2021. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/577.

MLA Handbook (7^th Edition):

Reuther, Jacquelyn. “INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU.” 2015. Web. 22 Jan 2021.

Vancouver:

Reuther J. INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU. [Internet] [Doctoral dissertation]. Texas Medical Center; 2015. [cited 2021 Jan 22]. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/577.

Council of Science Editors:

Reuther J. INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU. [Doctoral Dissertation]. Texas Medical Center; 2015. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/577

University of Ottawa

17. Racacho, Lemuel Jean. The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways .

Degree: 2015, University of Ottawa

URL: http://hdl.handle.net/10393/32187

► Brachydactyly type A1 (BDA1) is a rare autosomal dominant trait characterized by the shortening of the middle phalanges of digits 2-5 and of the proximal… (more)

Subjects/Keywords: Human genetics; Mutations; High-throughput sequencing; Cis-regulation; BMP-SMAD; Brachymesophalangies; Copy number variation; Targeted resequencing; IHH; GDF5; BMPR1B; Mendelian disorder

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Racacho, L. J. (2015). The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/32187

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Racacho, Lemuel Jean. “The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways .” 2015. Thesis, University of Ottawa. Accessed January 22, 2021. http://hdl.handle.net/10393/32187.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Racacho, Lemuel Jean. “The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways .” 2015. Web. 22 Jan 2021.

Vancouver:

Racacho LJ. The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways . [Internet] [Thesis]. University of Ottawa; 2015. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/10393/32187.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Racacho LJ. The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways . [Thesis]. University of Ottawa; 2015. Available from: http://hdl.handle.net/10393/32187

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universitat Pompeu Fabra

18. Rubio Pérez, Carlota, 1990-. Understanding the genomic makeup of tumors to guide personalized medicine.

Degree: Departament de Ciències Experimentals i de la Salut, 2017, Universitat Pompeu Fabra

URL: http://hdl.handle.net/10803/664287

► El càncer és una malaltia del genoma. L'estudi de les alteracions genòmiques dels tumors s’utilitza com a guia en varies estratègies de medicina de precisió,… (more)

Subjects/Keywords: Genomics; Cancer; Personalized medicine; Next-generation sequencing; Targeted therapies; Genòmica; Càncer; Medicina personalitzada; Seqûenciació de nova generació; Teràpies dirigides; 575

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APA (6^th Edition):

Rubio Pérez, Carlota, 1. (2017). Understanding the genomic makeup of tumors to guide personalized medicine. (Thesis). Universitat Pompeu Fabra. Retrieved from http://hdl.handle.net/10803/664287

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rubio Pérez, Carlota, 1990-. “Understanding the genomic makeup of tumors to guide personalized medicine.” 2017. Thesis, Universitat Pompeu Fabra. Accessed January 22, 2021. http://hdl.handle.net/10803/664287.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rubio Pérez, Carlota, 1990-. “Understanding the genomic makeup of tumors to guide personalized medicine.” 2017. Web. 22 Jan 2021.

Vancouver:

Rubio Pérez, Carlota 1. Understanding the genomic makeup of tumors to guide personalized medicine. [Internet] [Thesis]. Universitat Pompeu Fabra; 2017. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/10803/664287.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rubio Pérez, Carlota 1. Understanding the genomic makeup of tumors to guide personalized medicine. [Thesis]. Universitat Pompeu Fabra; 2017. Available from: http://hdl.handle.net/10803/664287

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

19. Bertrand, Sarah. Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma.

Degree: Docteur es, Biologie cellulaire, 2017, Université Grenoble Alpes (ComUE)

URL: http://www.theses.fr/2017GREAV033

►

Le lymphome est un cancer des ganglions lymphatiques, lieu de prolifération et différenciation des cellules immunitaires en particulier des lymphocytes B qui sont des cellules… (more)

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Le lymphome est un cancer des ganglions lymphatiques, lieu de prolifération et différenciation des cellules immunitaires en particulier des lymphocytes B qui sont des cellules productrices d'anticorps. Les lymphomes résultent de l’accumulation de mutations génétiques dans le génome d’une cellule B normale contribuant à la transformation en cellule B maligne. Cette cellule B dite transformée prolifère alors pour engendrer un clone de cellules B malignes qui s’accumulent au niveau des ganglions lymphatiques, formant alors une tumeur appelée ‘lymphome B’ (pour cancer lymphoïde issu de la transformation maligne des lymphocytes B). Le ganglion lymphatique normal a une structure histologique qui se décompose ainsi, du centre à la périphérie : le centre germinatif, la zone du manteau et la zone marginale. Les lymphomes B sont classés en différents sous-types histologiques en fonction de leur origine topographique au niveau du ganglion lymphatique et de leurs caractéristiques bio cliniques spécifiques. Parmi ces sous-types, une forme particulièrement agressive peut être distinguée : le lymphome à cellules du manteau. Ce sous-type de lymphome est caractérisé par des rechutes successives et une survie qui est généralement courte (médiane de survie de 4 à 5 ans) même si certains patients, avec des formes plus indolentes de lymphomes à cellules du manteau, présentent des survies prolongées (médiane de survie de 7 à 10 ans). Des biomarqueurs prédictifs de la courte survie manquent aujourd’hui, ce qui rend difficile la prise en charge optimisée des patients. Ce projet s’intéresse à cette question. Plus précisément, nous nous proposons de rechercher des mutations génétiques associées à la résistance thérapeutique. Notre approche sera basée sur le séquençage ciblé à haut débit du génome de cellules B tumorales issus de patients présentant des cas classiques du lymphomes à cellules du manteau mais aussi des cas plus particuliers comme ceux présentant des résistances thérapeutiques précoces, par exemple. Par cette approche dite de ‘cartographie’ à l’échelle du génome, nous espérons identifier des nouveaux prédicteurs moléculaires de la survie chez ces patients atteints de lymphome à cellules du manteau et également apporter de nouvelles connaissances dans l’interconnexion entre la génétique et l’épigénétique dans cette maladie.

Lymphoma is a cancer of the lymph nodes which are organs in which immune cells, particularly the antibody producing B cells, proliferate and differentiate before circulating in the blood and tissues to fight infection. B cell lymphoid cancers – ‘B cell lymphoma’ arise as a consequence of the occurrence of gene mutations in B cells. By affecting the functions of key B cell genes, these mutations drive the malignant transformation of the affected B cells which then begin to divide abnormally eventually destroying normal lymph node organization and function. The lymph node is divided into distinct micro-anatomical compartments or zones which are called (from the inner to outer most compartment – germinal…

Advisors/Committee Members: Callanan, Mary (thesis director).

Subjects/Keywords: Hématologie; Cancérologie; Génétique; Séquençage nouvelle génération; Epigénétique; Thérapies ciblées; Haematology; Cancer; Genetics; Next-Generation sequencing; Epigenetics; Targeted therapies; 610

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bertrand, S. (2017). Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma. (Doctoral Dissertation). Université Grenoble Alpes (ComUE). Retrieved from http://www.theses.fr/2017GREAV033

Chicago Manual of Style (16^th Edition):

Bertrand, Sarah. “Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma.” 2017. Doctoral Dissertation, Université Grenoble Alpes (ComUE). Accessed January 22, 2021. http://www.theses.fr/2017GREAV033.

MLA Handbook (7^th Edition):

Bertrand, Sarah. “Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma.” 2017. Web. 22 Jan 2021.

Vancouver:

Bertrand S. Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma. [Internet] [Doctoral dissertation]. Université Grenoble Alpes (ComUE); 2017. [cited 2021 Jan 22]. Available from: http://www.theses.fr/2017GREAV033.

Council of Science Editors:

Bertrand S. Séquençage ciblé en tant qu'outil diagnostique et pronostique dans le lymphome à cellules du manteau : Targeted deep sequencing as a diagnostic and prognostic tool in mantle cell lymphoma. [Doctoral Dissertation]. Université Grenoble Alpes (ComUE); 2017. Available from: http://www.theses.fr/2017GREAV033

University of New South Wales

20. Quek, Xiucheng. Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer.

Degree: Garvan Institute of Medical Research, 2017, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/58668 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46586/SOURCE02?view=true

► The recent rise of high-throughput sequencing technologies, paralleled with developments in computational biology, has provided an unprecedented amount of information on the roles of the… (more)

▼ The recent rise of high-throughput sequencing technologies, paralleled with developments in computational biology, has provided an unprecedented amount of information on the roles of the genome and transcriptome in human diseases. This has proven especially important for the treatment of cancer, where genomic diversity and acquired drug resistance are key challenges for development of successful therapies. In this thesis, we performed computational assessment of cancer transcriptomes, focusing on long non-coding RNAs (lncRNAs) as the master regulators of genome activity, in order to classify different types of skin cancer and examine mechanisms of adaptation to therapies.In our initial study, we performed the first whole-genome transcriptomic analysis of non-melanoma squamous cell carcinomas (NMSC-SCC) that distinguishes cancer types with similar clinical presentations. NMSC-SCC is a skin cancer that manifests as a spectrum of malignancies, ranging from actinic keratosis (AK) to intraepidermal carcinoma (IEC) and cutaneous squamous cell carcinoma (cSCC). We compared the transcriptomes of these malignancies, identified characteristic genes and pathways and defined IEC as a distinct malignancy. In addition, we characterised multiple lncRNAs, novel transcripts and fusion genes associated with NMSC-SCC pathogenesis.Next, we aimed to investigate development of resistance against targeted therapy in cancer over time. Targeted anti-cancer therapies work on specific parts of cancer pathways, but tumours develop resistance through stress-response pathways. To investigate the dynamics of these mechanisms, we studied a time course of resistance of two cancer cell-lines to four targeted therapies. Interestingly, resistant cells had initially downregulated DNA-repair genes and upregulated cell-proliferation genes followed by a complete reversal of their expression over time. This suggests that the fine-tuning of cancer genome mutation rates occurs as an adaptive strategy to treatment. Lastly, we identified several hypermutated genes with a role in development of resistance that present a potential target for novel cancer therapies.Finally, we provided the scientific community with a manually curated resource for lncRNAs with an experimentally proven function, lncRNAdb. This major update of the highly cited lncRNA database added a number of functional lncRNAs along with several usability upgrades, such as an inbuilt BLAST tool that allows database searches with nucleotide sequences. Updating lncRNAdb ensures its continuation as a reference database for lncRNAs research.Collectively, the thesis highlighted the application of computational method into the characterization of lncRNAs and cancer transcriptomics. Advisors/Committee Members: Dinger, Marcel, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Epstein, Richard John, Garvan Institute of Medical Research, Faculty of Medicine, UNSW.

Subjects/Keywords: long non-coding RNA; cancer trancriptomics; transcriptome; lncRNA; targeted therapy; resistant; squamous cell carcinoma; actinic keratosis; RNA Sequencing; intraepidermal carcinoma; lncRNAdb

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Quek, X. (2017). Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/58668 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46586/SOURCE02?view=true

Chicago Manual of Style (16^th Edition):

Quek, Xiucheng. “Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer.” 2017. Doctoral Dissertation, University of New South Wales. Accessed January 22, 2021. http://handle.unsw.edu.au/1959.4/58668 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46586/SOURCE02?view=true.

MLA Handbook (7^th Edition):

Quek, Xiucheng. “Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer.” 2017. Web. 22 Jan 2021.

Vancouver:

Quek X. Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer. [Internet] [Doctoral dissertation]. University of New South Wales; 2017. [cited 2021 Jan 22]. Available from: http://handle.unsw.edu.au/1959.4/58668 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46586/SOURCE02?view=true.

Council of Science Editors:

Quek X. Computational characterisation of the transcriptional landscape and long non-coding RNAs in cancer. [Doctoral Dissertation]. University of New South Wales; 2017. Available from: http://handle.unsw.edu.au/1959.4/58668 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46586/SOURCE02?view=true

Brno University of Technology

21. Sedlář, Karel. Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data.

Degree: 2019, Brno University of Technology

URL: http://hdl.handle.net/11012/137276

► Modern research in environmental microbiology utilizes genomic data, especially sequencing of DNA, to describe microbial communities. The field studying all genetic material present in an… (more)

Subjects/Keywords: metagenomika; cílené sekvenování; shotgun sekvenování; bipartitní graf; mikrobiální síť; binning; zpracování genomických signálů; metagenomics; targeted sequencing; shotgun sequencing; bipartite graph; microbial network; binning; genomic signal processing

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sedlář, K. (2019). Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data. (Thesis). Brno University of Technology. Retrieved from http://hdl.handle.net/11012/137276

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Sedlář, Karel. “Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data.” 2019. Thesis, Brno University of Technology. Accessed January 22, 2021. http://hdl.handle.net/11012/137276.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Sedlář, Karel. “Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data.” 2019. Web. 22 Jan 2021.

Vancouver:

Sedlář K. Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data. [Internet] [Thesis]. Brno University of Technology; 2019. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11012/137276.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Sedlář K. Metody pro komparativní analýzu metagenomických dat: Methods for Comparative Analysis of Metagenomic Data. [Thesis]. Brno University of Technology; 2019. Available from: http://hdl.handle.net/11012/137276

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

22. Matsudate, Yoshihiro. Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断.

Degree: 博士（医学）, 2017, Tokushima University / 徳島大学

URL: http://repo.lib.tokushima-u.ac.jp/110418

Subjects/Keywords: nevoid basal cell carcinoma syndrome; targeted exome sequencing; chromosomal microarray; PTCH1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Matsudate, Y. (2017). Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断. (Thesis). Tokushima University / 徳島大学. Retrieved from http://repo.lib.tokushima-u.ac.jp/110418

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Matsudate, Yoshihiro. “Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断.” 2017. Thesis, Tokushima University / 徳島大学. Accessed January 22, 2021. http://repo.lib.tokushima-u.ac.jp/110418.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Matsudate, Yoshihiro. “Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断.” 2017. Web. 22 Jan 2021.

Vancouver:

Matsudate Y. Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断. [Internet] [Thesis]. Tokushima University / 徳島大学; 2017. [cited 2021 Jan 22]. Available from: http://repo.lib.tokushima-u.ac.jp/110418.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Matsudate Y. Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome : ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断. [Thesis]. Tokushima University / 徳島大学; 2017. Available from: http://repo.lib.tokushima-u.ac.jp/110418

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Texas Medical Center

23. Laskowski, Tamara J. NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS.

Degree: PhD, 2014, Texas Medical Center

URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/468

► Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease characterized by thrombocytopenia, recurrent infections and increased autoimmunity. This disease is caused by mutations in… (more)

▼ Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease characterized by thrombocytopenia, recurrent infections and increased autoimmunity. This disease is caused by mutations in the WAS gene (WAS) which encodes for the WAS protein (WASp), exclusively expressed in hematopoietic cells and required for proper platelet production and lymphoid cell function. Approximately 11% of patients with WAS exhibit a phenomenon called Somatic Revertant Mosaicism which is characterized by the presence of lymphocytes which naturally revert back to normal phenotype by restoring WASp expression. To date, the mechanisms of this naturally-occurring gene therapy remains poorly understood, and the full extent of the repertoire of revertant genotypes has not yet been elucidated. The remaining 89% of WAS patients require treatment early in life, or the disease leads to premature death. At present, cure for WAS can only be attained through allogeneic stem cell transplantation or lentiviral hematopoietic stem cell gene therapy. In this work, we focused on both groups of WAS patients. In order to gain insight into the extent of the revertant repertoire in WAS revertant patients, we used next generation sequencing technology to analyze DNA from WASp⁺ T-cells isolated from two revertant patients carrying the same germline mutation. We identified over a hundred different revertant genotypes. In this report we describe those which directly reverted the original germline mutation, as well as those which are believed to provide a compensatory effect by inducing alternative splicing. Our findings represent, to our knowledge, the first report of ultra-deep analysis of somatic reversions in WAS patients. In our study of non-revertant WAS patients, we investigated restoration of T- and NK-cell functionality following an in vitro virus-free zinc-finger nuclease (ZFN)-mediated genome editing strategy for correction of WAS muations. We generated induced pluripotent stem cells (iPSC) from skin fibroblasts of a WAS patient carrying an insertional frame-shift mutation. Subsequently, a WAS-2A-eGFP transgene was targeted at the endogenous chromosomal location by homology-directed repair using ZFN, thereby correcting the gene defect and creating a GFP reporter for WASp expression. Hematopoietic progenitor cells were generated from WAS iPSC and gene-corrected iPSC (cWAS) in vitro via spin embryoid bodies. Human embryonic stem cell lines WA01 and WA09 were used as control. GFP expression was pronounced in all CD43+ hematopoietic lineages including myeloid, monocytic, lymphoid, erythroid and megakaryocytic lineages. Hematopoietic precursors were further cultured on OP9-DL1 to generate NK cells. NK cells were readily obtained from cWAS and WA01/WA09 progenitors, but to a far more limited extent from WAS progenitors. WAS-derived NK cells were unable to generate interferon-γ or tumor necrosis factor-α upon stimulation with K562. Cytokine production was restored in cWAS-derived NK… Advisors/Committee Members: Brian R. Davis, PhD, Phillip Carpenter, PhD, Laurence J. N. Cooper, MD, PhD.

Subjects/Keywords: Wiskott-Aldrich Syndrome; somatic reversion; genome editing; iPSC; hematopoietic progenitors; targeted endogenous integration; next-generation sequencing; Biology; Cell Biology; Immunity; Immunoprophylaxis and Therapy; Molecular Genetics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Laskowski, T. J. (2014). NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/468

Chicago Manual of Style (16^th Edition):

Laskowski, Tamara J. “NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS.” 2014. Doctoral Dissertation, Texas Medical Center. Accessed January 22, 2021. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/468.

MLA Handbook (7^th Edition):

Laskowski, Tamara J. “NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS.” 2014. Web. 22 Jan 2021.

Vancouver:

Laskowski TJ. NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS. [Internet] [Doctoral dissertation]. Texas Medical Center; 2014. [cited 2021 Jan 22]. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/468.

Council of Science Editors:

Laskowski TJ. NATURAL AND EXOGENOUS GENOME EDITING IN WISKOTT-ALDRICH SYNDROME PATIENT CELLS. [Doctoral Dissertation]. Texas Medical Center; 2014. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/468

Université Paris-Sud – Paris XI

24. Truffaux, Nathalene. Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children.

Degree: Docteur es, Oncologie, 2014, Université Paris-Sud – Paris XI

URL: http://www.theses.fr/2014PA11T022

►

Le gliome infiltrant du tronc cérébral est une tumeur rare, non opérable et inéluctablement fatale. En raison du manque de ressource biologique disponible, aucun progrès… (more)

▼

Le gliome infiltrant du tronc cérébral est une tumeur rare, non opérable et inéluctablement fatale. En raison du manque de ressource biologique disponible, aucun progrès dans la compréhension de la biologie de ces tumeurs n’a été fait jusqu’à ces dernières années, laissant la radiothérapie pour seul traitement efficace, et seulement transitoirement. Enfin, grâce à la mise en place de collecte d’échantillons de gliomes infiltrant du tronc cérébral au diagnostic ou à l’autopsie, un nombre sans précédent d’analyses biologiques et génomiques a pu être mené et améliorer la connaissance de ces tumeurs. Si ces études ont montré que ces gliomes pédiatriques étaient bien différents de ceux de l’adulte, elles ont aussi fait apparaître la présence d’anomalies génétiques récurrentes spécifiques de ces tumeurs sous-tentorielles. Ainsi le Platelet-Derived Growth Factor Receptor Alpha (PDGFRα) est apparu comme cible prédominante dans ces tumeurs compte tenu des nombreuses anomalies génétiques constatées. La recherche d’un médicament efficace pouvant inhiber cette voie nous a conduit à évaluer l’effet du dasatinib qui est un inhibiteur multi-ciblé. Nous en rapportons ici l’efficacité in vitro sur de nouvelles lignées cellulaires de gliomes infiltrants du tronc cérébral établies à partir de biopsies stéréotaxiques réalisées au diagnostic. Sachant néanmoins que les thérapies ciblées restent peu efficaces en clinique quand elles sont utilisées seules, nous mettons en évidence l’intérêt de combiner le dasatinib avec un inhibiteur de MET, 2ème oncogène fréquemment amplifié dans ces tumeurs. D’autre part, une stratégie originale de criblage médicamenteux a été mise en œuvre. Celle-ci a permis de définir de manière fonctionnelle de nouveaux médicaments potentiellement efficaces dans les gliomes infiltrants du tronc cérébral, incluant les inhibiteurs d’Histone deacetylases (HDAC), les inhibiteurs des Cyclin-Dependent Kinases (CDK) ou encore les inhibiteurs du protéasome. Enfin par la technique de séquençage génome-entier, de nouvelles anomalies génétiques jamais rencontrées dans aucun autre cancer ont été détectées. Parmi celles-ci se trouvent des mutations d’histone H3K27M dont la fréquence élevée (80%) suggère leur rôle fondamental dans la genèse de ces tumeurs. Des mutations activatrices d’ACVR1/ALK2 ont été également mises en évidence. Celles-ci représentent désormais de nouvelles cibles à explorer.Ce travail de thèse rapporte la recherche de nouvelles cibles thérapeutiques d’une part, via une approche exploratoire par criblage médicamenteux et recherche d’anomalies génétiques par séquençage « génome-entier », et d’autre part, via une approche de validation préclinique sur le plan des thérapies ciblées de type inhibiteurs de tyrosine-kinases.

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, unresectable and universally fatal tumor. Due to the lack of available material, no improvements have been made in the knowledge of the biology of this tumor until recent years, leaving radiotherapy as the only efficient treatment, and only…

Advisors/Committee Members: Grill, Jacques (thesis director).

Subjects/Keywords: Gliome infiltrant du tronc cérébral; Thérapie ciblée; Criblage fonctionnel; Dasatinib; Séquençage; Génome-entier; ACVR1; Diffuse Intrinsic Pontine Glioma (DIPG),; Targeted therapy; Functional screening; Dasatinib; Whole; Genome sequencing; ACVR1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Truffaux, N. (2014). Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children. (Doctoral Dissertation). Université Paris-Sud – Paris XI. Retrieved from http://www.theses.fr/2014PA11T022

Chicago Manual of Style (16^th Edition):

Truffaux, Nathalene. “Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children.” 2014. Doctoral Dissertation, Université Paris-Sud – Paris XI. Accessed January 22, 2021. http://www.theses.fr/2014PA11T022.

MLA Handbook (7^th Edition):

Truffaux, Nathalene. “Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children.” 2014. Web. 22 Jan 2021.

Vancouver:

Truffaux N. Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children. [Internet] [Doctoral dissertation]. Université Paris-Sud – Paris XI; 2014. [cited 2021 Jan 22]. Available from: http://www.theses.fr/2014PA11T022.

Council of Science Editors:

Truffaux N. Nouvelles cibles thérapeutiques dans les gliomes infiltrants du tronc cérébral de l'enfant : New therapeutic targets in diffuse intrinsic pontine glioma in children. [Doctoral Dissertation]. Université Paris-Sud – Paris XI; 2014. Available from: http://www.theses.fr/2014PA11T022

25. Nicolaou, N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.

Degree: 2016, University Utrecht

URL: http://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; http://dspace.library.uu.nl/handle/1874/328921

► This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition… (more)

▼ This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition drives the development of congenital anomalies of the kidney and urinary tract, but the clinical variability and large genetic heterogeneity requires a sophisticated approach to detect the genetic causes. In this thesis we sequenced 208 genes suspected to be involved in CAKUT in 453 patients with CAKUT, in order to detect genetic variants that are likely to disrupt gene function and lead to CAKUT. We identified multiple rare genetic variants that are predicted to disrupt the function of their corresponding gene. However, the results of a statistical analysis suggest that rare genetic variants in these tested genes are not more frequent in patients in comparison to healthy individuals. This suggests that none of these genes plays a major role in the development of CAKUT. It could be that variants in other genes may have a bigger effect on the risk of developing CAKUT, or that the risk of CAKUT depends on a combination of multiple genetic factors with a small effect and a number of environmental factors. Therefore, future investigations should test the role of all genes in CAKUT as well as environmental factors using even more patients with CAKUT. We also present two individual patients with a unique combination of symptoms that has not been reported in the literature before. We describe the first application of whole genome sequencing in a patient with kidney disease to identify the genetic cause, which resulted in the identification of variants in multiple genes that are functionally related to the phenotypes observed in the patient. In another patient we identified and characterized a single genetic mutation that completely stops the expression of an essential protein in the kidney and lung tissue. The mutation leads to a new multi-organ disorder observed in our patient, including interstitial lung disease and congenital nephrotic syndrome. This discovery enabled the use of genetic testing in our hospital for other newborns with similar symptoms, thereby facilitating an early diagnosis and enabling the risk estimation of having more affected offspring. Further, we discuss the tools that are available to scientists today to unravel the function of newly identified genes and study the alterations in gene function that may be caused by such uncharacterized genetic variants. We performed functional characterization tests to elucidate the impact of the variants in a single gene detected in several CAKUT patients. Here, we provide experimental evidence suggesting that the variants exert disruptive effects on, at least, one of the functions of the gene. Our results open a big question about the possibility of microscopic, hair-like structures on eukaryotic cells, called cilia, having an effect on the development of CAKUT. Advisors/Committee Members: Knoers, N.V.A.M., Giles, R.H., Renkema, K.Y..

Subjects/Keywords: CAKUT; NGS; cilia; kidney development; targeted sequencing; nephrotic syndrome; WGS

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nicolaou, N. (2016). Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; http://dspace.library.uu.nl/handle/1874/328921

Chicago Manual of Style (16^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Doctoral Dissertation, University Utrecht. Accessed January 22, 2021. http://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; http://dspace.library.uu.nl/handle/1874/328921.

MLA Handbook (7^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Web. 22 Jan 2021.

Vancouver:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Internet] [Doctoral dissertation]. University Utrecht; 2016. [cited 2021 Jan 22]. Available from: http://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; http://dspace.library.uu.nl/handle/1874/328921.

Council of Science Editors:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Doctoral Dissertation]. University Utrecht; 2016. Available from: http://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; http://dspace.library.uu.nl/handle/1874/328921

University of Lund

26. Jönsson, Jenny-Maria. Intrinsic subtypes and prognostic implications in epithelial ovarian cancer.

Degree: 2015, University of Lund

URL: https://lup.lub.lu.se/record/8499980 ; https://portal.research.lu.se/ws/files/3008585/8499981.pdf

► Ovarian cancer is the seventh most common cancer in women globally, with approximately 240,000 new cases annually. Although a rare disease, it is the most… (more)

▼ Ovarian cancer is the seventh most common cancer in women globally, with approximately 240,000 new cases annually. Although a rare disease, it is the most lethal gynecologic malignancy. Unspecific symptoms result in late diagnosis and a generally poor prognosis. However, ovarian cancer is a heterogeneous disease comprising different disease entities, which is of importance in clinical decision-making as well as in research. This thesis describes explorative approaches to investigate the ovarian cancer heterogeneity in a hereditary ovarian cancer subset and in histopathological and molecular subtypes of ovarian cancer. In study I, a gene expression profile differentiating the rare subgroup of Lynch syndrome-associated ovarian cancer from a matched sporadic cohort was identified. The Lynch syndrome-related expression profile was associated with proliferation and cell death processes. An external dataset was used to refine the gene expression profile, but validation with immunohistochemical staining of key proteins did not reveal any differences between the hereditary and sporadic cases. A distinct cluster of hereditary serous and endometrioid cancers was seen, whereas clear cell carcinomas (OCCCs) clustered together, whether hereditary or sporadic. In study II, gene expression profiling of OCCCs revealed extensive inter-tumor heterogeneity. Targeted deep sequencing of 60 cancer-related genes in an OCCC cohort revealed frequent mutations of chromatin remodeling genes, including mutations not previously reported in ovarian cancer. These results remain to be validated. Study III outlined gene expression profiles in malignant, borderline, and benign serous ovarian tumors. Pre-defined molecular subtypes of ovarian cancer as well as intrinsic breast cancer subtypes were applied to our cohort. Associations between the most aggressive ovarian cancer subtypes and the basal-like breast cancer subtype were identified. The results were validated using a large, external dataset. Furthermore, associations between borderline ovarian tumors and the luminal A breast cancer subtype were discovered. The luminal A breast cancer subtype characterizes hormone receptor positive breast cancer. In study IV, we therefore outlined the protein expression of estrogen receptor (ER) α, ERβ, the progesterone receptor (PR), and the androgen receptor (AR) as well as the prognostic effect of receptor expression in serous and endometrioid ovarian cancer. Expression of PR and AR was associated with a favorable prognosis, and co-expression of PR and AR conferred an additional prognostic benefit. The mRNA levels of the encoding genes were investigated in the molecular subtypes of ovarian cancer using an external dataset. The expression varied between the different subtypes, but no prognostic benefit of dual high PGR and AR levels were revealed. In conclusion these studies further characterize the ovarian cancer heterogeneity, and support that future ovarian cancer studies need to be stratified for both histopathologic subtypes and molecular features

Subjects/Keywords: Cancer and Oncology; ovarian cancer; gene expression profiling; Lynch syndrome; targeted deep sequencing; chromatin remodeling; molecular subtypes; endocrine receptors; prognostic factors; tumor heterogeneity

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❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jönsson, J. (2015). Intrinsic subtypes and prognostic implications in epithelial ovarian cancer. (Doctoral Dissertation). University of Lund. Retrieved from https://lup.lub.lu.se/record/8499980 ; https://portal.research.lu.se/ws/files/3008585/8499981.pdf

Chicago Manual of Style (16^th Edition):

Jönsson, Jenny-Maria. “Intrinsic subtypes and prognostic implications in epithelial ovarian cancer.” 2015. Doctoral Dissertation, University of Lund. Accessed January 22, 2021. https://lup.lub.lu.se/record/8499980 ; https://portal.research.lu.se/ws/files/3008585/8499981.pdf.

MLA Handbook (7^th Edition):

Jönsson, Jenny-Maria. “Intrinsic subtypes and prognostic implications in epithelial ovarian cancer.” 2015. Web. 22 Jan 2021.

Vancouver:

Jönsson J. Intrinsic subtypes and prognostic implications in epithelial ovarian cancer. [Internet] [Doctoral dissertation]. University of Lund; 2015. [cited 2021 Jan 22]. Available from: https://lup.lub.lu.se/record/8499980 ; https://portal.research.lu.se/ws/files/3008585/8499981.pdf.

Council of Science Editors:

Jönsson J. Intrinsic subtypes and prognostic implications in epithelial ovarian cancer. [Doctoral Dissertation]. University of Lund; 2015. Available from: https://lup.lub.lu.se/record/8499980 ; https://portal.research.lu.se/ws/files/3008585/8499981.pdf

27. Nicolaou, N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.

Degree: 2016, University Utrecht

URL: https://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; https://dspace.library.uu.nl/handle/1874/328921

► This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition… (more)

▼ This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition drives the development of congenital anomalies of the kidney and urinary tract, but the clinical variability and large genetic heterogeneity requires a sophisticated approach to detect the genetic causes. In this thesis we sequenced 208 genes suspected to be involved in CAKUT in 453 patients with CAKUT, in order to detect genetic variants that are likely to disrupt gene function and lead to CAKUT. We identified multiple rare genetic variants that are predicted to disrupt the function of their corresponding gene. However, the results of a statistical analysis suggest that rare genetic variants in these tested genes are not more frequent in patients in comparison to healthy individuals. This suggests that none of these genes plays a major role in the development of CAKUT. It could be that variants in other genes may have a bigger effect on the risk of developing CAKUT, or that the risk of CAKUT depends on a combination of multiple genetic factors with a small effect and a number of environmental factors. Therefore, future investigations should test the role of all genes in CAKUT as well as environmental factors using even more patients with CAKUT. We also present two individual patients with a unique combination of symptoms that has not been reported in the literature before. We describe the first application of whole genome sequencing in a patient with kidney disease to identify the genetic cause, which resulted in the identification of variants in multiple genes that are functionally related to the phenotypes observed in the patient. In another patient we identified and characterized a single genetic mutation that completely stops the expression of an essential protein in the kidney and lung tissue. The mutation leads to a new multi-organ disorder observed in our patient, including interstitial lung disease and congenital nephrotic syndrome. This discovery enabled the use of genetic testing in our hospital for other newborns with similar symptoms, thereby facilitating an early diagnosis and enabling the risk estimation of having more affected offspring. Further, we discuss the tools that are available to scientists today to unravel the function of newly identified genes and study the alterations in gene function that may be caused by such uncharacterized genetic variants. We performed functional characterization tests to elucidate the impact of the variants in a single gene detected in several CAKUT patients. Here, we provide experimental evidence suggesting that the variants exert disruptive effects on, at least, one of the functions of the gene. Our results open a big question about the possibility of microscopic, hair-like structures on eukaryotic cells, called cilia, having an effect on the development of CAKUT. Advisors/Committee Members: Knoers, N.V.A.M., Giles, R.H., Renkema, K.Y..

Subjects/Keywords: CAKUT; NGS; cilia; kidney development; targeted sequencing; nephrotic syndrome; WGS

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nicolaou, N. (2016). Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; https://dspace.library.uu.nl/handle/1874/328921

Chicago Manual of Style (16^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Doctoral Dissertation, University Utrecht. Accessed January 22, 2021. https://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; https://dspace.library.uu.nl/handle/1874/328921.

MLA Handbook (7^th Edition):

Nicolaou, N. “Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies.” 2016. Web. 22 Jan 2021.

Vancouver:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Internet] [Doctoral dissertation]. University Utrecht; 2016. [cited 2021 Jan 22]. Available from: https://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; https://dspace.library.uu.nl/handle/1874/328921.

Council of Science Editors:

Nicolaou N. Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies. [Doctoral Dissertation]. University Utrecht; 2016. Available from: https://dspace.library.uu.nl/handle/1874/328921 ; URN:NBN:NL:UI:10-1874-328921 ; urn:isbn:978-94-6295-457-1 ; URN:NBN:NL:UI:10-1874-328921 ; https://dspace.library.uu.nl/handle/1874/328921

28. Tlemsani, Camille. Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers.

Degree: Docteur es, Génétique cellulaire et moléculaire, 2018, Sorbonne Paris Cité

URL: http://www.theses.fr/2018USPCB077

► La neurofibromine, produit du gène NF1, agit comme un inhibiteur de la voie RAS-MAPK (Mitogen-activated protein kinases), voie majeure de la cancérogenèse. Le gène NF1… (more)

▼ La neurofibromine, produit du gène NF1, agit comme un inhibiteur de la voie RAS-MAPK (Mitogen-activated protein kinases), voie majeure de la cancérogenèse. Le gène NF1 est donc un gène suppresseur de tumeurs. Des mutations constitutionnelles hétérozygotes perte-de-fonction de NF1 causent la neurofibromatose de type 1 (NF1 ; MIM#162200). Cette maladie rare prédispose notamment au développement de tumeurs des gaines nerveuses. Des mutations somatiques de NF1 ont par ailleurs été décrites dans des cancers sporadiques, hors contexte de neurofibromatose. Des données récentes de la littérature confirment que NF1 est un gène suppresseur de tumeurs crucial en oncologie. L'implication de la voie RAS-MAPK dans les cancers bronchiques non à petites cellules (CBNPC) est bien caractérisée avec la mise en évidence de mutations somatiques activatrices spécifiques de la voie, notamment des oncogènes EGFR, KRAS et BRAF dans les adénocarcinomes pulmonaires. Cependant, l'implication du gène NF1 a été peu étudiée dans les CBNPC. Nous avons confirmé l'implication de NF1 dans le développement des adénocarcinomes bronchiques par une approche ciblée de NGS (Next Generation Sequencing) sur une cohorte de 138 échantillons tumoraux : 36 altérations somatiques (26%) de NF1 ont été retrouvées dont 25 mutations ponctuelles (parmi lesquelles 4 homozygotes) et 11 délétions. Ces altérations étaient majoritairement exclusives de mutations affectant d'autres effecteurs de la voie RAS-MAPK. Il était retrouvé un nombre plus important d'altérations de NF1 dans les échantillons de patients ayant reçu une chimiothérapie. Une corrélation génotype-phénotype a pu être établie : il s'agissait en majorité d'hommes (72%), fumeurs (75%) avec une survie sans progression et une survie globale significativement meilleures que les patients KRAS mutés. Afin de déterminer les conséquences fonctionnelles des altérations de NF1, nous avons établi des modèles cellulaires mutés dans NF1 grâce au système d'édition du génome CRISPR/Cas9. Trois lignées de carcinomes bronchiques non à petites cellules ont été modifiées génétiquement. Nous avons notamment évalué les conséquences de l'inactivation bi- ou mono-allélique de NF1 réalisée respectivement par CRISPR/Cas9 et Nickase. Les western blot ont confirmé la perte d'expression partielle ou complète de la neurofibromine en cas de mutations mono- ou bi-alléliques du gène NF1 ainsi qu'une activation de la voie RAS-MAPK avec un ratio pERK/ERK augmenté en cas de mutations. Nous avons observé que les clones NF1-/- présentaient un phénotype plus agressif en termes de migration, invasion et prolifération que les clones NF1+/- ou sauvages. L'analyse différentielle des transcriptomes a montré des profils transcriptomiques distincts en cas d'altérations homozygotes ou hétérozygotes de NF1 ainsi que dans les cellules sauvages ; les profils transcriptomiques des clones sauvages étaient plus proches des clones avec mutations hétérozygotes de NF1. Des approches pharmacologiques in vitro sur nos modèles cellulaires transgéniques pour tester la… Advisors/Committee Members: Pasmant, Eric (thesis director), Vidaud, Michel (thesis director).

Subjects/Keywords: Carcinomes bronchiques non à petites cellules; Nf1; Voie RAS-MAPK; Next generation sequencing; CRISPR/Cas9; Thérapies ciblées; Modèles murins; Non-small cell lung cancers; Nf1; RAS-MAPK pathway; Next generation sequencing; CRISPR Cas9; Targeted therapies; Transcriptomic analysis; Murine models; 616.991

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❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tlemsani, C. (2018). Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers. (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2018USPCB077

Chicago Manual of Style (16^th Edition):

Tlemsani, Camille. “Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers.” 2018. Doctoral Dissertation, Sorbonne Paris Cité. Accessed January 22, 2021. http://www.theses.fr/2018USPCB077.

MLA Handbook (7^th Edition):

Tlemsani, Camille. “Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers.” 2018. Web. 22 Jan 2021.

Vancouver:

Tlemsani C. Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers. [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2018. [cited 2021 Jan 22]. Available from: http://www.theses.fr/2018USPCB077.

Council of Science Editors:

Tlemsani C. Caractérisation moléculaire et étude des conséquences fonctionnelles des mutations somatiques du gène NF1 dans les carcinomes bronchiques non à petites cellules : Characterization of molecular and functional consequences of somatic NF1 mutations in non- small cell lung cancers. [Doctoral Dissertation]. Sorbonne Paris Cité; 2018. Available from: http://www.theses.fr/2018USPCB077

29. Alexander, John. Statistical methodology for the analysis of genomic data.

Degree: 2016, Democritus University of Thrace (DUTH); Δημοκρίτειο Πανεπιστήμιο Θράκης (ΔΠΘ)

URL: http://hdl.handle.net/10442/hedi/39736

►

My PhD thesis focuses on introducing a novel algorithm and software to prioritize variants from genomic data according to their functional significance. As there already… (more)

▼

My PhD thesis focuses on introducing a novel algorithm and software to prioritize variants from genomic data according to their functional significance. As there already exist several annotation databases and algorithms that use different approaches to predict the functional significance of variants, there exists considerable variability in variant annotations and predictions. Therefore, there is a need to combine the outputs of several algorithms and annotation databases in order to optimize accuracy. In order to achieve this, we implement and aggregate multiple prediction algorithm scores, conservation scores, allelic frequencies, clinical information and additional open-source annotations using accessible databases via ANNOVAR software into our Variant Ranker algorithm. Using our Variant Ranker web-tool, users can prioritize variants according to their novelty, deleteriousness and conservation thus identifying variants that potentially carry the signature of the disease under study. The biological significance of these prioritized variants can be further investigated using our Network Analyser module and other gene ontology tools. We expect out tool will be particularly useful to biologist/clinicians with limited bioinformatics experience.First the algorithm is presented and then its application is described using different genomic analysis including (i) Tourette syndrome resequencing data, (ii) Alzheimer-type family exome sequencing data and (iii) Whole genome healthy brain analysis.

Η διδακτορική μου διατριβή επικεντρώνεται εισαγωγή ενός νέου αλγορίθμου και λογισμικού για την ιεράρχηση παραλλαγών από γονιδιωματικά δεδομένα με βάση τη λειτουργική τους σημασία. Καθώς ήδη υπάρχουν αρκετές βάσεις δεδομένων σχολιασμού και αλγόριθμοι που χρησιμοποιούν διαφορετικές προσεγγίσεις για να προβλέψουν τη λειτουργική σημασία των παραλλαγών, υπάρχει αξιοσημείωτη μεταβλητότητα στα πεδία του σχολιασμού και πρόβλεψης των παραλλαγών. Ως εκ τούτου, υπάρχει ανάγκη να συνδυαστούν τα αποτελέσματα των αλγορίθμων και των βάσεων δεδομένων σχολιασμού, προκειμένου να βελτιστοποιηθεί η ακρίβεια. Για να επιτευχθεί αυτό, εφαρμόσαμε και ενσωματώσαμε βαθμολογίες πολλών αλγορίθμων πρόβλεψης, βαθμολογίες συντήρησης, αλληλικές συχνότητες, κλινικές πληροφορίες και επιπλέον σχολιασμούς ανοιχτού κώδικα, χρησιμοποιώντας προσβάσιμες βάσεις δεδομένων, μέσω του λογισμικού ANNOVAR στον δικό μας αλγόριθμο με το όνομα Variant Ranker. Χρησιμοποιώντας το διαδικτυακό μας εργαλείο με όνομα Variant Ranker, οι χρήστες μπορούν να τοποθετήσουν κατά σειρά προτεραιότητας παραλλαγές με βάση την καινοτομία τους, το πόσο επιβλαβείς και συντηρημένες είναι, εντοπίζοντας έτσι παραλλαγές που δυνητικά θα φέρουν την υπογραφή της υπό μελέτη νόσου. Η βιολογική σημασία αυτών των ταξινομημένων κατά σειρά προτεραιότητας παραλλαγών μπορεί να διερευνηθεί περεταίρω χρησιμοποιώντας το στοιχείο Network Analyser και άλλα εργαλεία γονιδιακής οντολογίας. Αναμένουμε ότι το εργαλείο μας θα είναι ιδιαίτερα χρήσιμο σε βιολόγους/κλινικούς ιατρούς με περιορισμένη εμπειρία στον τομέα της…

Subjects/Keywords: Γονιδιωματική ανάλυση; Αλληλούχιση επόμενης γενιάς; Στοχευμένη-αλληλούχιση; Αλληλούχιση ολόκληρου του γονιδιώματος; Αλληλούχιση εξονίων; Βιοπληροφορική; Διαδικτυακό εργαλείο; Κατάταξη; Ιεράρχηση; Σύνδρομο Tourette; Νόσος Alzheimer; Άνοια; Νευροεκφυλισμός; Ανάλυση μονοπατιών; Ανάλυση δικτύων; Γενεαλογία ανάλυση; Ανάλυση ασθενών-ατόμων ελέγχου; Λειτουργική εμπλουτισμός; Genomic analysis; Next generation sequencing; targeted-sequencing; Whole genome sequencing; exome sequencing; Bioinformatics; web-tool; Ranking; prioritization; Tourette syndrome; Alzheimer’s disease; Dementia; Neurodegeneration; functional enrichment; Pathway analysis; Network analysis; pedigree analysis; case-control analysis

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Alexander, J. (2016). Statistical methodology for the analysis of genomic data. (Thesis). Democritus University of Thrace (DUTH); Δημοκρίτειο Πανεπιστήμιο Θράκης (ΔΠΘ). Retrieved from http://hdl.handle.net/10442/hedi/39736

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Alexander, John. “Statistical methodology for the analysis of genomic data.” 2016. Thesis, Democritus University of Thrace (DUTH); Δημοκρίτειο Πανεπιστήμιο Θράκης (ΔΠΘ). Accessed January 22, 2021. http://hdl.handle.net/10442/hedi/39736.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Alexander, John. “Statistical methodology for the analysis of genomic data.” 2016. Web. 22 Jan 2021.

Vancouver:

Alexander J. Statistical methodology for the analysis of genomic data. [Internet] [Thesis]. Democritus University of Thrace (DUTH); Δημοκρίτειο Πανεπιστήμιο Θράκης (ΔΠΘ); 2016. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/10442/hedi/39736.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Alexander J. Statistical methodology for the analysis of genomic data. [Thesis]. Democritus University of Thrace (DUTH); Δημοκρίτειο Πανεπιστήμιο Θράκης (ΔΠΘ); 2016. Available from: http://hdl.handle.net/10442/hedi/39736

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

30. Zhan, Xiaowei. Statistical Methods and Analysis in Next Generation Sequencing.

Degree: PhD, Biostatistics, 2014, University of Michigan

URL: http://hdl.handle.net/2027.42/107129

► Next generation sequencing (NGS) is a technology that advances our knowledge of human medical genetics with unprecedented amount of data. This vast amount of data… (more)

▼ Next generation sequencing (NGS) is a technology that advances our knowledge of human medical genetics with unprecedented amount of data. This vast amount of data presents challenges to existing statistical methods. In this dissertation, I present three studies that demonstrate methods for efficiently analyzing NGS data using both simulated and real data. In the first study, I develop ancestry inference method using small amounts of sequence data. In comparison to microarray experiments, sequencing data produce uneven coverage and genotypes with higher error rates than those traditionally used for principal components analysis (PCA) of genetic ancestry. I overcome some of these challenges using a novel statistical method modeling sequence data directly without relying on intermediate genotype calls. My method achieves high accuracy in simulated data based on the Human Genome Diversity Panel as well as in a targeted sequencing study of age related macular degeneration. In our age-related macular degeneration study, our approach helps discover a high-risk rare variant in the Complement 3 gene. In the second chapter, I develop a model-based ancestry inference method that improves upon previous work described in the first study. It is based on a likelihood-based model of ancestral location, using sequencing data as input. Without losing accuracy, it increases computational efficiency. For each sample, a parallelizable optimization algorithm can infer ancestry using a fraction of the computational resources required for PCA-based methods. Evaluation using in the Human Genome Diversity Panel and age-related macular degeneration data set demonstrates its accuracy and efficiency. In the final study, I develop an improved genotype call method for low-coverage sequencing data. As high quality reference panels grow, it is helpful to incorporate these into genotype calling of new samples. Using a coalescent based simulation and real data from the 1000 Genomes Project, I evaluate the utility of my method (which uses a panel of previously sequenced samples) to improve analyses of samples sequenced at various depths. The improvement in accuracy and computation time will be measured as a function of reference panel size. This work will be useful to investigators undertaking sequencing and analysis of new human samples. Advisors/Committee Members: Abecasis, Goncalo (committee member), Burmeister, Margit (committee member), Boehnke, Michael Lee (committee member), Kang, Hyun Min (committee member).

Subjects/Keywords: Next Generation Sequencing; Ancestral Inference; Age-related Macular Degeneration; Imputation; Targeted Sequencing; Genetic Association Studies; Public Health; Health Sciences

…62 3.2.4 AMD targeted-sequencing data set… …41 Figure 2-8 Estimation of ancestry for 3,159 samples in the AMD targeted sequencing… …Genome Diversity Panel as well as in a targeted sequencing study of age related macular… …apply it to a targeted-sequencing study of the Agerelated Macular Degeneration (AMD)… …can efficiently estimate sample ancestries using sequence data such as targeted sequencing…

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APA (6^th Edition):

Zhan, X. (2014). Statistical Methods and Analysis in Next Generation Sequencing. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/107129

Chicago Manual of Style (16^th Edition):

Zhan, Xiaowei. “Statistical Methods and Analysis in Next Generation Sequencing.” 2014. Doctoral Dissertation, University of Michigan. Accessed January 22, 2021. http://hdl.handle.net/2027.42/107129.

MLA Handbook (7^th Edition):

Zhan, Xiaowei. “Statistical Methods and Analysis in Next Generation Sequencing.” 2014. Web. 22 Jan 2021.

Vancouver:

Zhan X. Statistical Methods and Analysis in Next Generation Sequencing. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2027.42/107129.

Council of Science Editors:

Zhan X. Statistical Methods and Analysis in Next Generation Sequencing. [Doctoral Dissertation]. University of Michigan; 2014. Available from: http://hdl.handle.net/2027.42/107129

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