Thesis: S.M., Massachusetts Institute of Technology, Computation for Design and Optimization Program, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 65-74). / Cancer sequencing efforts have largely focused on profiling somatic variants in the protein-coding genome and characterizing their functional impact. In this study, we develop a computational pipeline to identify non-coding mutational drivers across multiple tumor types. We describe the non-coding mutational profiles of 854 samples, spread across 15 tumor types, in the context of their respective tissue type-specific reference epigenomes, using recent pan-cancer whole-genome sequencing data. We develop a novel method to detect significantly recurrent non-coding mutations by reestimating the background mutation density while adjusting for epigenomic covariates. Existing databases on enhancer-gene links allow us to capture the convergence of disparate mutations onto downstream target genes. We then systematically identify key immunomodulatory and tumor-suppressive genes enriched for non-coding mutations in their regulatory neighborhood and evaluate these in a pan-cancer context. Taken together, we show that low-frequency alterations converge into high-frequency recurrent events on downstream targets through tissue-specific regulatory interactions. / by Karthik Murugadoss. / S.M.
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/111510 |
| Date | January 2017 |
| Creators | Murugadoss, Karthik |
| Contributors | Manolis Kellis., Massachusetts Institute of Technology. Computation for Design and Optimization Program., Massachusetts Institute of Technology. Computation for Design and Optimization Program. |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 74 pages, application/pdf |
| Rights | MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission., http://dspace.mit.edu/handle/1721.1/7582 |
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