The candidate is an accomplished gastroenterology fellow with a prior background in cancer biology and a commitment to a career in clinical and translational research in the study of sessile serrated polyps. The candidate's long-term career goal is to become an independently funded physician scientist, devoting more than 75% of his time to establish and maintain a clinical research program in gastrointestinal cancer precursor lesions. The candidate's short-term career goals are to 1) build large longitudinal cohort coupled with host genetic data;2) design and interpret genetic data, including development of novel genomics software;3) develop mouse models of cancer derived from human genetic data 4) acquire new laboratory skills in DNA damage signaling and microscopy 5) produce the data and publication record necessary for a successful R01 application. This application outlines the institutional commitment, research plan, career development activities and key mentors involved to ensure the candidate accomplishes these goals. In prior work, the candidate has demonstrated that individuals with serrated polyposis harbor germline loss-of-function mutations in key senescence pathways. This finding, in agreement with mouse models, provides the first genetic framework for the heritable nature of serrated polyposis. Nonetheless, data regarding the genetic influences for the development of sporadic sessile serrated polyps are lacking. In this proposal, the candidate seeks to identify such genetic factors through a translation approach of human genetics, animal models, and in vitro experiments. The specific goals of this study are to 1) estimate the contribution of rare loss-of-function mutations in oncogene-induced senescence pathways in the development of sessile serrated polyps in average-risk individuals and 2) evaluate the mechanism through in vivo and in vitro experiments by which a newly implicated tumor suppressor promotes the development of serrated neoplasia. As an integral part of this proposal, the candidate's career development will be complemented by participation in advanced coursework and research seminars to develop expertise in genetic epidemiology, systems biology, and computer programming. A formal mentorship committee and advisory team, consisting of multidisciplinary experts in next-generation sequencing technologies, genetic epidemiology, mouse models of disease, and the microscopy will provide supervision, guidance, and assistance for the candidate to achieve his goals. The research environment, which includes the MGH GI Unit, MGH Cancer Center, and the Harvard School of Public Health will provide a rich, collaborative, and supportive atmosphere to ensure the candidate's success. Through this award, the candidate will become an independent clinical investigator by contributing to our understanding of the genetics of serrated polyps through a series of translational studies that leverage human genetic data with in vivo and in vitro models.
Sessile serrated adenomas represent a newly recognized precursor lesion to colon cancer, accounting for 2% of polyps found during screening colonoscopies and 20% of all colorectal cancers. In this proposal, we will leverage human genomic data with animal disease models to comprehensively investigate the role of genetics in the development of these lesions. Our study has the potential to lead to the use of a person's genomic information to assess the risk of developing this new type of precancerous polyp and uncover novel genes that predispose to this condition.