Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers

Abstract

Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD− tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD− and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD− and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD−/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution. Significance: These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.

A balancing act: how whole-genome doubling and aneuploidy interact in human cancer

“…To address this intriguing question, we recently analyzed 5,586 clinical tumor samples that had not undergone WGD (WGD-) and 3,435 tumors that had (WGD+) from The Cancer Genome Atlas (TCGA), across 22 tumor types [ 6 ]. WGD- and WGD+ tumors showed distinct aneuploidy patterns; WGD+ tumors were more chromosomally unstable and were more permissive to aneuploidy, presenting not only more aneuploidies in general but also a wider variety of events.…”

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

“…Numerous studies show that tetraploidization is an important pathway to aneuploidy in human cancer cells, which is based on direct observations of this process in tumor cell lines (Cimini et al, 1999; Shi and King, 2005) and deduced from distribution of chromosome numbers in different tumors (Prasad et al, 2022; Storchova and Kuffer, 2008). In order to investigate theoretically the role of this pathway and its interplay with other processes, our model can be extended by including whole genome duplication as an additional choice of cell fate at each division.…”

Double-checking chromosome segregation

“…On one hand, preventing premature NER on incompletely separated chromosomes during normal anaphase protects against polyploidy. Whole-genome duplication is a common evolutionary event that is also frequent in >30% of human tumors early in tumorigenesis and is thought to promote chromosomal instability and metastasis by providing a selective advantage in certain contexts ( Ben-David and Amon, 2020 ; Bielski et al, 2018 ; Dewhurst et al, 2014 ; Gemble et al, 2022 ; Newcomb et al, 2021 ; Prasad et al, 2022 ; Priestley et al, 2019 ; Storchova and Pellman, 2004 ; Zack et al, 2013 ). On the other hand, spatiotemporal control of NER would allow the correction of anaphase lagging chromosomes and prevent formation of micronuclei ( Afonso et al, 2014 ).…”