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Cell. 2019 May 30;177(6):1375-1383. doi: 10.1016/j.cell.2019.05.005.

Identifying Epistasis in Cancer Genomes: A Delicate Affair.

Author information

1
Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Program in Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.
4
Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands.
5
Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Faculty of EEMCS, Delft University of Technology, Delft, 2628 CD, the Netherlands. Electronic address: l.wessels@nki.nl.
6
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Program in Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Cancer Cell Map Initiative, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.

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.

KEYWORDS:

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

PMID:
31150618
DOI:
10.1016/j.cell.2019.05.005

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