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Nat Genet. 2018 Aug;50(8):1189-1195. doi: 10.1038/s41588-018-0165-1. Epub 2018 Jul 16.

Genome doubling shapes the evolution and prognosis of advanced cancers.

Author information

1
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Genentech, San Francisco, CA, USA.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA.
8
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. taylorb@mskcc.org.
9
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. taylorb@mskcc.org.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. taylorb@mskcc.org.

Abstract

Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors. The variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD predicted for increased morbidity across cancer types, including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers, independently of established clinical prognostic factors. We conclude that WGD is highly common in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types.

PMID:
30013179
PMCID:
PMC6072608
DOI:
10.1038/s41588-018-0165-1
[Indexed for MEDLINE]
Free PMC Article

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