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Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostat

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Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostat Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostate Cancer Thomas A. White A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2013 Reading Committee: Peter S. Nelson, Chair Janet L. Stanford Raymond J. Monnat Jay A. Shendure Program Authorized to Offer Degree: Molecular and Cellular Biology ©Copyright 2013 Thomas A. White University of Washington Abstract Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostate Cancer Thomas A. White Chair of the Supervisory Committee: Peter S. Nelson, MD Novel functionally altered transcripts may be recurrent in prostate cancer (PCa) and may underlie lethal and advanced disease and the neuroendocrine small cell carcinoma (SCC) phenotype. We conducted an RNASeq survey of the LuCaP series of 24 PCa xenograft tumors from 19 men, and validated observations on metastatic tumors and PCa cell lines. Key findings include discovery and validation of 40 novel fusion transcripts including one recurrent chimera, many SCC-specific and castration resistance (CR) -specific novel splice isoforms, new observations on SCC-specific and TMPRSS2-ERG specific differential expression, the allele-specific expression of certain recurrent non- synonymous somatic single nucleotide variants (nsSNVs) previously discovered via exome sequencing of the same tumors, rgw ubiquitous A-to-I RNA editing of base excision repair (BER) gene NEIL1 as well as CDK13, a kinase involved in RNA splicing, and the SCC expression of a previously unannotated long noncoding RNA (lncRNA) at Chr6p22.2. Mechanistic investigation of the novel lncRNA indicates expression is regulated by derepression by master neuroendocrine regulator RE1-silencing transcription factor (REST), and may regulate some genes of axonogenesis and angiogenesis. Taken together these variant transcripts offer insight into aggressive metastatic PCa, both broadly and with regard to castration-resistant and neuroendocrine disease. TABLE OF CONTENTS Page List of Figures …………………………………………………………………………….ii List of Tables .………………………………………...…………...………………….… iii List of Abbreviations …………………………………...……………………………..…iv Acknowledgements ……………………………………..……………………………….vi Dedication ……………………………………………..…………………………….....viii Chapter 1: Introduction .…………………………………………………………………. 1 Significance ...…………………………………………………..…………..………….… 3 Prostate adenocarcinoma and neuroendocrine prostate cancer ………….....………….… 4 Risk factors for prostate cancer development …………………………...…......…..……. 6 Prevalence and roles of somatic mutations and transcript alterations in prostate cancer….............................................................................................................................. 9 LuCaP xenografts: surgically acquired models of metastatic prostate cancer ……......... 13 References ..…………………………………………………………...……………...… 16 Chapter 2: RNASeq of LuCaP prostate cancers reveals recurrent expression of novel functional variants ………………………………….…………...…………..………….. 20 Summary ………………………………………………………..……………………… 20 Introduction .………………………………………………………...………………….. 22 Results …………………………………………………………………..….…………... 24 Discussion ….……………………………………………………...………...…………. 30 Materials and Methods …..……………………………….…………………...……...… 35 References ..……………………………………………………………...…………...… 40 Chapter 3: lncRNA 6p22.2: A novel neuroendocrine PCa specific long noncoding RNA………………………………………………………………………………….… 54 Summary ..………………………………………………………………..………….… 55 Introduction ………………………………………………………………..…………... 55 Results …………………………………………………………………………….....… 56 Discussion ……….…………………………………………………………….........… 57 Materials and Methods …………………………………………………..…………..… 60 References ..……………………………………………………………………….....… 63 Chapter 4: Conclusions and Perspectives …..………………………………..……...… 66 i LIST OF FIGURES Page Chapter 2 Figure 1: Unsupervised clustering of expression of top 1,000 most variable transcripts..46 Figure 2: Differentially expressed genes in neuroendocrine LuCaPs vs Adenocarcinoma, by significantly enriched KEGG pathway ..……...…………………...……………..….47 Figure 3: Differentially expressed genes in TMPRSS2-ERG (+) vs (-) LuCaPs ………48 Figure 3: Neuroendocrine-specific lincRNA at chr6 p22.2 .……………………..….…. 49 Figure 4: STK39-COL5A2 rearrangement transcript …….…………….…...……….… 50 Figure 5: Proportion of expressed genes harboring somatic non-synonymous single nucleotide variants which display variant allele expression fraction ≥ 10%, by LuCaP. 51 Chapter 3 Figure 1: Genomic context of novel neuroendocrine-specific LincRNA ………...……. 61 Figure 2: RT-PCR of lncRNA and neuroendocrine markers in BPH-1 lincRNA overexpression ………………………………………………………………………..... 62 Figure 3: REST repressesion of lncRNA 6p22.2 expression ………………………..… 63 ii LIST OF TABLES Page Chapter 2 Table 1: Next-generation sequencing of prostate cancer xenografts …………………...40 Table 2: Expression of most frequently recurrent non-synonymous single nucleotide variants …………………………………………………………………..…………..… 41 Table 3: Novel rearrangement transcript expression in LuCaP prostate cancers (excluding TMPRSS2-ERG) ……………………………………………..………….… 43 Table 4: Neuroendocrine-specific novel splice junctions …………….…….……...….. 44 Table 5: Castration resistance specific novel splice junctions ………....…….…..……. 45 Table S1: Composite list of transcripts among the top 500 most abundant in one or more LuCaPs ………………………………………………………………………………..... 75 Table S2: Differential expression in neuroendocrine vs adenocarcinoma LuCaPs ..... 109 Table S3: Differential expression in TMPRSS2-ERG rearrangement (+) vs. (-) LuCaPs ......................................................................................................................................... 135 Chapter 3 Table 1: Annotated lncRNAs differentially expressed in neuroendocrine vs. adenocarcinoma LuCaPs………………………………………………….……..…...… 59 Table 2: REST-regulated gene expression in neuroendocrine vs. adenocarcinoma LuCaPs ……………………………………………………………………..…..………. 60 iii LIST OF ABBREVIATIONS ADT: androgen deprivation therapy AR: androgen receptor AS: alternate splicing BPH: benign prostatic hyperplasia CNV: copy number variation CR: castration resistant CRPC: castration resistant prostate cancer CS: castration sensitive DHT: dihydroxy testosterone DRE: digital rectal exam FISH: fluorescent in situ hybridization lncRNA: long noncoding RNA NCI: National Cancer Institute NEPC: neuroendocrine prostate cancer nsSNV: non-synonymous single nucleotide variant PCa: prostate cancer PCR: polymerase chain reaction PSA: prostate specific antigen RP: radical prostatectomy RPKM: reads per kilobase per million aligned reads RT-PCR: real-time PCR SCC: small cell carcinoma iv SCLC: small cell lung carcinoma SNV: single nucleotide variant XRT: external beam radiation therapy v Acknowledgements The author wishes to express sincere gratitude to his advisor Dr. Peter S. Nelson for his substantial support, miraculous patience and critical contribution to the development of this work. Professor Janet L. Stanford’s contribution of dual mentorship throughout this and prior work is also tremendously appreciated. The support and feedback of supervisory committee members Drs. Robert Eisenman, Ray Monnat and Jay Shendure are greatly valued. Regarding scientific accomplishments, this project would have been impossible without the efforts of Drs. Robert Vessella and Colm Morrisey and the selfless contributions of many victims of prostate cancer to the University of Washington Rapid Autopsy Program. Akash Kumar of the Shendure lab, who led the Exome sequencing sister study to this RNAseq project, and his lab colleagues Sarah Ng, Choli Lee and Alex MacKenzie contributed substantially to the foundation of this work. Matthew Fitzgibbon, Nigel Clegg and Jerry Davison of Dr. Martin McIntosh’s team made the analysis of RNAseq data possible, and made substantial intellectual contributions. Jeff Delrow and Jerry (Andy) Marty of the FHCRC Core Facilities, who performed high- throughput sequencing and their colleague Elizabeth Jensen who reliably performed Sanger sequencing made high quality data a matter of routine and are greatly appreciated. Drs. Larry True and Funda Vakar-Lopez provided invaluable pathology support and feedback. In the Nelson lab, virtually every member has made important contributions to this project, from expression microarray hybridization and analysis, to training or guidance on nearly every bench method, to moral support. This work would not have been completed without the support of Drs. Jared Lucas, Ilsa Coleman, Roger Coleman, vi Daniella Bianchi-Frias, Clint Matson, Robin Tharakan, Dapei Li, Roland Huber, Susana Hernandez-Lopez, Aric Zhao, Song Zhao as well as former members Drs. Eric Bluemn, James Dean, Ryan Gordon, Renee Chmelar, and Karl Thoreson and Andrew Morgan. The support of Ruthy Dumpit in particular spanned the breadth of the project and beyond, and was absolutely invaluable. The support of Alex Moreno both administrative and as a friend are greatly appreciated. Dr. Elahe Mostaghel and her lab members Arja Kaipainen, Qi Tain, Steven Mongovin and Ailin Zhang have also provided valuable support and feedback, as have countless other faculty, postdocs, scientists, students and staff at the FHCRC. The University of Washington Molecular and Cell Biology (MCB) Program provided a robust and flexible structure for the completion of this degree. MaryEllin
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