Identifying Epistasis in Cancer Genomes: A Delicate Affair

Joris van de Haar, Sander Canisius, Michael K. Yu, Emile E. Voest, Lodewyk F.A. Wessels, Trey Ideker

Research output: Contribution to journalArticleScientificpeer-review

18 Citations (Scopus)

Abstract

Recent studies of the tumor genome seek to identify cancer pathways as groups of genes in which mutations are epistatic with one another or, specifically, “mutually exclusive.” Here, we show that most mutations are mutually exclusive not due to pathway structure but to interactions with disease subtype and tumor mutation load. In particular, many cancer driver genes are mutated preferentially in tumors with few mutations overall, causing mutations in these cancer genes to appear mutually exclusive with numerous others. Researchers should view current epistasis maps with caution until we better understand the multiple cause-and-effect relationships among factors such as tumor subtype, positive selection for mutations, and gross tumor characteristics including mutational signatures and load. An analysis of cancer genomes provides a rethink of how to interpret mutations epistatic to one another as well as the effects on phenotypes and therapeutic vulnerabilities.

Original languageEnglish
Pages (from-to)1375-1383
Number of pages9
JournalCell
Volume177
Issue number6
DOIs
Publication statusPublished - 30 May 2019

Keywords

  • cancer
  • cancer genome
  • co-occurrence
  • epistasis
  • genome
  • mutation
  • mutation load
  • mutual exclusivity
  • subtype
  • systems biology

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