Signatures of accelerated somatic evolution in gene promoters in multiple cancer types

Kyle S. Smith, Vinod K. Yadav, Brent S. Pedersen, Rita Shaknovich, Mark W. Geraci, Katherine S. Pollard, Subhajyoti De

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Cancer-associated somatic mutations outside protein-coding regions remain largely unexplored. Analyses of the TERT locus have indicated that non-coding regulatory mutations can be more frequent than previously suspected and play important roles in oncogenesis. Using a computational method called SASE-hunter, developed here, we identified a novel signature of accelerated somatic evolution (SASE) marked by a significant excess of somatic mutations localized in a genomic locus, and prioritized those loci that carried the signature in multiple cancer patients. Interestingly, even when an affected locus carried the signature in multiple individuals, the mutations contributing to SASE themselves were rarely recurrent at the base-pair resolution. In a pan-cancer analysis of 906 samples from 12 tumor types, we detected SASE in the promoters of several genes, including known cancer genes such as MYC, BCL2, RBM5 and WWOX. Nucleotide substitution patterns consistent with oxidative DNA damage and local somatic hypermutation appeared to contribute to this signature in selected gene promoters (e.g. MYC). SASEs in selected cancer gene promoters were associated with over-expression, and also correlated with the age of onset of cancer, aggressiveness of the disease and survival. Taken together, our work detects a hitherto under-appreciated and clinically important class of regulatory changes in cancer genomes.

Original languageEnglish (US)
Pages (from-to)5307-5317
Number of pages11
JournalNucleic Acids Research
Volume43
Issue number11
DOIs
StatePublished - Apr 17 2015
Externally publishedYes

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Clonal Evolution
Genes
Neoplasms
Mutation
Neoplasm Genes
Age of Onset
Base Pairing
Open Reading Frames
DNA Damage
Carcinogenesis
Nucleotides
Genome
Survival

ASJC Scopus subject areas

  • Genetics

Cite this

Smith, K. S., Yadav, V. K., Pedersen, B. S., Shaknovich, R., Geraci, M. W., Pollard, K. S., & De, S. (2015). Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. Nucleic Acids Research, 43(11), 5307-5317. https://doi.org/10.1093/nar/gkv419

Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. / Smith, Kyle S.; Yadav, Vinod K.; Pedersen, Brent S.; Shaknovich, Rita; Geraci, Mark W.; Pollard, Katherine S.; De, Subhajyoti.

In: Nucleic Acids Research, Vol. 43, No. 11, 17.04.2015, p. 5307-5317.

Research output: Contribution to journalArticle

Smith, KS, Yadav, VK, Pedersen, BS, Shaknovich, R, Geraci, MW, Pollard, KS & De, S 2015, 'Signatures of accelerated somatic evolution in gene promoters in multiple cancer types', Nucleic Acids Research, vol. 43, no. 11, pp. 5307-5317. https://doi.org/10.1093/nar/gkv419
Smith KS, Yadav VK, Pedersen BS, Shaknovich R, Geraci MW, Pollard KS et al. Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. Nucleic Acids Research. 2015 Apr 17;43(11):5307-5317. https://doi.org/10.1093/nar/gkv419
Smith, Kyle S. ; Yadav, Vinod K. ; Pedersen, Brent S. ; Shaknovich, Rita ; Geraci, Mark W. ; Pollard, Katherine S. ; De, Subhajyoti. / Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 11. pp. 5307-5317.
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