A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases.

TitleA Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases.
Publication TypeJournal Article
Year of Publication2018
AuthorsZhang, Y, Yang, L, Kucherlapati, M, Chen, F, Hadjipanayis, A, Pantazi, A, Bristow, CA, Lee, EA, Mahadeshwar, HS, Tang, J, Zhang, J, Seth, S, Lee, S, Ren, X, Song, X, Sun, H, Seidman, J, Luquette, LJ, Xi, R, Chin, L, Protopopov, A, Li, W, Park, PJ, Kucherlapati, R, Creighton, CJ
JournalCell Rep
Date Published2018 Jul 10
KeywordsBase Sequence, Carcinogenesis, DNA Copy Number Variations, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Genes, Neoplasm, Genome, Human, Humans, Neoplasms

A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes-including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)-show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA.

Alternate JournalCell Rep
PubMed ID29996110
PubMed Central IDPMC6092947
Grant ListK01 AG051791 / AG / NIA NIH HHS / United States
K22 CA193848 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States

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