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FRS2 Is an Oncogene in High Grade Ovarian Cancer

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FRS2 Is an Oncogene in High Grade Ovarian Cancer FRS2 Is an Oncogene in High Grade Ovarian Cancer The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Luo, Leo Y. 2015. FRS2 Is an Oncogene in High Grade Ovarian Cancer. Doctoral dissertation, Harvard Medical School. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:15821602 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Abstract Ovarian cancer is the most common cause of gynecologic cancer death in the United States. Despite aggressive surgical cytoreduction and chemotherapy, ovarian cancer remains one of the most lethal cancer types due to advanced stages at diagnosis and lack of effective systemic therapy. High-grade serous ovarian cancers (HGSOC) are characterized by widespread recurrent regions of copy number gain and loss. Here we interrogated 50 genes that are recurrently amplified in HGSOC and essential for cancer proliferation and survival in ovarian cancer cell lines. FRS2 is one of the 50 genes located on chromosomal region 12q15 that is focally amplified in 12.5% of HGSOC. We found that FRS2 amplified cancer cell lines are dependent on FRS2 expression and that FRS2 overexpression in immortalized human cell lines conferred the ability to grow in an anchorage independent manner and as tumors in immunodeficient mice. FRS2, an adaptor protein in the FGFR pathway, induces downstream activation of Ras-MAPK pathway. These observations identify FRS2 as an oncogene in a subset of HGSOC that harbor FRS2 amplifications. This study underlines the power of complementary genomic approaches that use efficient high-throughput methods to assess functional consequences of genomic alterations and develop therapeutic targets toward clinical translation. The discovery of FRS2 as an oncogene also highlights adaptor proteins as a new class of oncogenes that can become the next generation of therapeutic targets. 2 Acknowledgments This thesis could not have happened without the help of the following people. First of all, I am deeply grateful to my advisor, Professor William Hahn for his mentorship and unfailing support. He leads by example and sets a high bar for future physician-scientists. He challenges me to approach science with rigor and fearlessness, taught me the importance of precision in communicating scientific results and ideas, and showed me the rapidly changing landscape of cancer research and its transformative power in the clinic. I want to thank my collaborator, friend, Hiu Wing (Tony) Cheung, for instilling excitement into this project and being a great mentor. Although we only worked side-by-side for two months, I have learned from Tony through many discussions over the experimental techniques and research directions. This project would not have been completed without my colleague Eejung Kim, who carried the project over its final stretch toward publication. I thank the other co-authors of the manuscript, Barbara Weir, Gavin Dunn, and Rhine Shen, and fellow members of the Hahn lab, Susan Moody, Diane Shao, Xiaoxing Wang, for providing valuable guidance on experiments and scientific directions. I have benefited greatly from discussions on science, medicine, and life with my classmates, faculty members, and staffs of the Health Sciences and Technology program at Harvard Medical School, especially my advisors David Ting and Rick Mitchell. This project was generously supported by a research fellowship from the Howard Hughes Medical Institute. I thank Melanie Daub and William Galey at HHMI for their roles in making the fellowship year a fantastic experience. Lastly I am forever indebted to my parents, who offer unconditional support and taught me the value of scholarship. 3 Table of Contents Page No. Abstract 1 Acknowledgement 3 Table of Contents 4 Glossary of Abbreviations 5 Introduction 6 Materials and Methods 11 Results 17 Discussion 22 Conclusion 29 Summary 30 Figures and Legends 32 References 45 4 Glossary HEK293 Human embryonic kidney 293 cells AKT AK-strain thymoma gene, also known as protein kinase B CCLE Cancer Cell Line Encyclopedia CRKL Crk-like protein ERK1/2 Extracellular signal-regulated kinases 1 and 2 FGFR Fibroblast growth factor receptor FRS2 Fibroblast growth factor receptor Substrate 2 GAB2 GRB2-associated-binding protein 2 GRB2 Growth factor receptor-bound protein 2 HA1E Human embryonic kidney cells immortalized with SV40TAg and hTERT HA1E-A Human embryonic kidney cells immortalized with SV40TAg and hTERT, transformed with myristolated AKT HA1E-M Human embryonic kidney cells immortalized with SV40TAg and hTERT, transformed with MEK-DD (constitutively active MEK) IOSE Immortalized ovarian surface epithelium PARP-1 Poly-ADP-ribose polymerase 1 SH2 Src Homology 2 domain SH3 Src Homology 3 domain shRNA short hairpin RNA TCGA The Cancer Genome Atlas project 5 Introduction Ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death in the United States (1). In 2014, ovarian cancer accounts for 21,980 estimated new cases and 14,270 estimated deaths (2). Histologically, ovarian epithelial carcinomas can be divided into high-grade serous, low-grade serous, endometrioid, mucinous, and clear cell subtypes. Clinically, high-grade serous ovarian cancer (HGSOC) accounts for 70-80% of all ovarian carcinomas and is characterized by its de novo invasive nature. The origin of high-grade serous ovarian cancer (HGSOC) has thought to be from ovarian epithelial cells, however, more recent studies have proposed the origin to be in fallopian tube fimbria (3). Due to similar clinical behavior, epithelial carcinoma, fallopian tubal, and peritoneal carcinomas are considered a single clinical entity for treatment. The first-line chemotherapy treatment for advanced epithelial ovarian cancer is a platinum plus taxane combination. HGSOCs are initially sensitive to platinum-taxane treatment but develop resistance in approximately 25% of patients within six months (4). To this date, ovarian cancer remains one of the most lethal cancer types due to the advanced stage at diagnosis and lack of effective systemic therapy. It is known that ovarian cancer is characterized by a combination of germline and somatic mutations. Germline mutations in BRCA1/2 account for approximately 13% of HGSOCs, while somatic mutations are largely dominated by TP53 mutations (5, 6). A smaller proportion of HGSOCs are attributable to germline mutations in mismatch repair genes such as MSH2, MSH6, MLH2, and PMS2 (Lynch syndrome) (5). Several common chromosomal region copy number variations have also been observed in ovarian cancers. However, most of the somatic aberrations have not been well characterized. 6 Comprehensive characterization and analysis of the human cancer genome Due to a significant decrease in the cost of high-throughput sequencing technologies, it has become possible to comprehensively characterize and analyze the cancer genome. The Cancer Genome Atlas (TCGA) project, sponsored by the National Cancer Institute and the National Human Genome Research Institute, began a series of large-scale sequencing studies to catalogue all genetic alterations responsible for cancer. The pilot studies focused on the characterization of two tumor types, glioblastoma multiforme and ovarian carcinoma. Over 500 primary tumor samples from each tumor type underwent whole-exome sequencing, copy number variation analysis, gene expression profiling, and DNA methylation analysis (7, 8). All data from the publication were made available to the public through the TCGA Data Portal. Since the pilot phase, TCGA project has expanded the characterization effort and published the data on other major cancer types, including colon and rectal cancer, breast cancer, squamous cell lung cancer, and lung adenocarcinoma (9-12). The information generated by sequencing thousands of tumor samples presents an opportunity as well as a challenge. It has pushed for development of newer computational analytic tools to decode the cancer genome, including newer methods to detect mutations and copy number variations. The wealth of data points and robust analytic methods provide a unique opportunity to investigate the biology and pathogenesis of cancer. Genomic landscape of ovarian carcinoma To catalog all the molecular aberrations present in HGSOC, The TCGA network performed a large-scale, multiplatform genomic profiling study (13). A total of 489 clinically- 7 annotated, stage II-IV, HGSOC tumors were analyzed for copy number variation, mRNA expression, microRNA expression, and DNA promoter methylation. Whole-exome sequencing was performed on 316 of these tumor samples. The results and correlated clinical outcomes were made accessible to the public. The mutation analysis from sequenced HGSOCs has revealed a predominance of TP53 mutations in 96% of the sequenced tumors, similar to what has been described in previous literature. Approximately 9% of BRCA1 and 8% of BRCA2 contained germline mutations. Another six genes were found to be significantly mutated, although to a much lesser extent: RB1 (2%), NF1 (4%), FAT3 (6%), CSMD3 (6%), GABRA6 (2%), and CKD12 (3%). Further analysis has shown that these mutations, in addition to mRNA expression aberrations, represent alterations in key cancer-associated signaling pathways, such as RB signaling,
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