Distinct aneuploid karyotypes are universally selected for across cancers

Abstract

Aneuploid karyotype evolution leads to immense variability in cancer patient prognosis, so characterizing relevant trends has been an important objective (1-9). Recurrent chromosome gains and losses as well as oncogenic mutations have been associated with specific cancers (10-14), but a general trend in aneuploidy evolution has not yet been identified. Here we show a universal selection principle for karyotypes composed entirely of disomies and trisomies that is conserved across many different cancer types and even in yeast. This finding is surprising enough on its own, as cancers do not typically have generalized trends, but we also see that these karyotypes exhibit a 3 times lower mutation rate of the cancer suppressor gene TP53 compared to other aneuploid karyotypes. We find that, in general, karyotypes composed of combinations of any two chromosome copy numbers, termed binary karyotypes, make up over three-quarters of the Mitelman database, which we explain by a 15% increased fitness relative to other aneuploid karyotypes. In conclusion, our results reveal binary karyotypes as a distinct category of aneuploid karyotypes that are tolerated by p53 and universally selected for independent of encoded genes or any other chromosome-specific feature, shifting the current paradigm of aneuploid cell classification.