Whole-genome duplication shapes the aneuploidy landscape of human cancers

Abstract

Aneuploidy – a hallmark of cancer – has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.

An elevated rate of whole-genome duplications associated with carcinogen exposure in Black cancer patients

“…S7A-C). However, cancers that have undergone WGD events have consistently been observed to exhibit a higher aneuploidy burden than WGD-negative cancers 56,66 . Indeed, when we analyzed the aneuploidy levels in WGD-positive and WGD-negative cancers separately, the differences between Black and white patients were muted (Fig.…”

“…The causes and consequences of WGDs are poorly understood; mutations in TP53 have been linked with WGD development but other genetic and environmental causes remain obscure 43,47,48 . WGDs enhance tumor adaptability and increase metastatic dissemination, potentially by enhancing tumor heterogeneity and allowing cancers to sample a wider range of karyotypes 47,[49][50][51] . Approximately 30% of tumors exhibit WGDs, but whether patient race or ethnicity is associated with these events is unknown 47 .…”

Copy number footprints of platinum-based anticancer therapies

“…This event of whole-genome doubling (WGD) constitutes a hallmark of cancer genome evolution [14][15][16]. By doubling the size of the genome, the WGD is thought to relax the selective pressure on large SVs, in particular deletions, effectively increasing genome instability and plasticity in the evolution of cancer cells [17][18][19].…”

Copy number footprints of platinum-based anticancer therapies

“…This event of whole-genome doubling (WGD) constitutes a hallmark of cancer genome evolution (Bielski et al, 2018;Gerstung et al, 2020;Priestley et al, 2019). By doubling the size of the genome, the WGD is thought to relax the selective pressure on large SVs, in particular deletions, effectively increasing genome instability and plasticity in the evolution of cancer cells (López et al, 2020;Prasad et al, 2021;Dewhurst et al, 2014).…”