Oncomorphic Tp53 mutations in advanced serous ovarian carcinomas

for advising me on the oncology related aspects of my project. From numerous discussions to collecting patient samples and allowing me to watch a surgery, his input was instrumental. I would also like to thank my committee members, Dr. me with encouragement and experimental insight. friends I have made along the way, who have given me unwavering support. My parents planted the curiosity for knowledge deep inside my brain when I was young, and I would not be where I am today without them. Lastly, I would like to sincerely thank the numerous patients and their families that allowed me to perform my studies. My research would not have been possible without their generosity. iv ABSTRACT The tumor suppressor gene TP53 sits at the crux of response to cellular stresses. This is the most frequently inactivated gene in human tumors, being the target of somatic mutations. The protein product of TP53 is p53, and plays a crucial role in anti-proliferative signals through the induction of apoptosis, senescence, and cell-cycle arrest when activated by stresses such as genotoxic chemotherapeutic drugs. Therefore, the status of TP53 mutations in a tumor has profound implications for the tumorigenic potential as well as the response to anti-cancer therapies. Indeed, numerous studies have shown a predictive and prognostic value of TP53 mutations to the response to chemotherapy, but just as many studies show no significant contribution of TP53 mutations to chemotherapy response. This controversy is partly due to the lack of standard methods of TP53 mutation detection, but more importantly, it is due to the categorization of all TP53 mutations into one group. Certain mutations in TP53 can confer to the mutant protein new, gained activities, not normally present in the WT p53 protein. These have been commonly called " gain of function " (GOF) p53 proteins, and some GOF p53 proteins can even confer oncogenic properties. However, not all gained functions are necessarily implicated in oncogenicity. Using stringent criteria, we have defined a select group of GOF TP53 mutations that do function as oncogenic proteins as oncomorphic TP53 mutations. In this work, we utilize data available from a large patient population through The Cancer Genome Atlas (TCGA) as well as data available from the University of Iowa Gynecologic Oncology Tumor Bank to examine the association of v oncomorphic TP53 mutations with patient outcome using advanced serous ovarian cancer as a model. We demonstrate that oncomorphic …