Genome doubling shapes the evolution and prognosis of advanced cancers

Ploidy abnormalities are a hallmark of human cancers, 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 the pathogenesis of affected cancers after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wildtype tumors and, in such cases, was associated with an E2F-mediated G1 arrest defect, though 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 risk of death in tumors pan-cancer, a negative impact independent of established clinical prognostic factors in multiple cancer types including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers. WGD is one of the most common genomic events in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types.