Abstract
Whole genome doubling (WGD) is among the most prevalent genomic alterations in cancer, present in approximately one third of patients at the time of diagnosis. WGD provides cancer cells with a selective advantage, by protecting against mutations in haploinsufficient genes or buffering deleterious mutations. Factors which negatively select against the WGD state are largely unexplored. Here, we review evidence indicating that cells with WGD are more sensitive to resource restriction than their non-WGD counterparts. We hypothesize that differences in energy access across tissue sites explain differences in cancer ploidy and aneuploidy at the time of detection. By shedding light on the energetic constraints that influence cancer ploidy and aneuploidy, this perspective highlights a critical yet underexplored area of cancer research.