Understanding Ancestral Contribution to Lung Adenocarcinoma

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PROJECT SUMMARY/ABSTRACT Although there are existing epidemiological studies of disparities in cancer incidence and outcomes, there are very few studies of disparities in cancer genomes, which requires both germline, somatic, and clinical data from the same patients. However, studying ancestry-specific genomic alterations is one of the most effective ways to understand the underpinning mechanisms in cancer disparity, and develop potential prevention and therapeutics strategies. Dr. Carrot-Zhang and others evaluated genetic ancestry effects on somatic alterations among 10,678 patients across 33 cancer types from The Cancer Genome Atlas, and highlighted novel ancestry-specific evolutionary trajectories from pan-cancer and tissue-specific analyses. We also suggested that ancestry associations were profoundly tissue specific, and therefore, more samples from diverse ancestries are required for tissue-specific analyses. To that extent, this proposal is based on large sequencing data sets composed of 1,153 lung cancer patients from Mexico and Colombia, and 60,085 lung cancer samples from Foundation Medicine. Our overall goal is to understand the well-known, but mysterious, population-specific genomic differences in lung adenocarcinoma. Our first aim is to systematically characterize the landscape of ancestry effects on genomic features of lung adenocarcinoma, as we are well powered to detect new associations. Then in the second aim, Dr. Carrot-Zhang will develop a novel statistical method leveraging the local ancestry (ancestry of a genomic region) from ancestry-admixed populations to infer the heritability of ancestry-associated somatic features. We will also explore the potential mechanisms underlying genomic differences related to ancestry. Our third aim is to elucidate the influence of ancestry on clinical outcome, in order to improve prognostics and precision medicine for the minority populations. Dr. Carrot-Zhang’s long-term career goal is to improve cancer prevention, early detection and treatment by integrating computational biology, germline genetics, and somatic genomics approaches to understand the mechanisms underlying cancer initiation and progression. The K99 award will further prepare her for a successful independent research career. Dr. Carrot-Zhang’s training will be carried out under the extraordinary mentorship of Dr. Matthew Meyerson (cancer genomics), and an advisory committee consisting of Drs. Alexander (Sasha) Gusev (population genetics and statistical genetics), Rameen Beroukhim (cancer biology), Heng Li (computational method development), and David Kwiatkowski (clinical oncology). The proposed research plan will be facilitated by the outstanding institutional environment of the Dana-Farber Cancer Institute and the Broad Institute. The scientific collaboration with Foundation Medicine will provide exceptional resources for cancer genomics and ancestry-related analyses. The proposed professional development plan will enhance Dr. Carrot- Zhang’s career advancement in laboratory management, grant-writing and leadership.