Global impact of somatic structural variation on the DNA methylome of human cancers.

TitleGlobal impact of somatic structural variation on the DNA methylome of human cancers.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhang, Y, Yang, L, Kucherlapati, M, Hadjipanayis, A, Pantazi, A, Bristow, CA, Lee, EAlice, 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, Park, PJ, Kucherlapati, R, Creighton, CJ
JournalGenome Biol
Date Published2019 Oct 15
KeywordsCpG Islands, Epigenome, Genomic Structural Variation, Humans, Neoplasms

BACKGROUND: Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored.

RESULTS: By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration.

CONCLUSION: Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.

Alternate JournalGenome Biol
PubMed ID31610796
PubMed Central IDPMC6792267
Grant ListT32 HG002295 / HG / NHGRI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
CA125123 / CA / NCI NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States

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