Whole-Genome Doubling and Aneuploidy in Human Cancer

In a new editorial paper, researchers from Tel Aviv University discuss a recent study exploring how whole-genome doubling shapes the aneuploidy landscape of human cancers.

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Whole-genome doubling (WGD) and aneuploidy are two common genomic alterations that occur in human cancers. WGD is a macro-evolutionary event that results in the duplication of the entire genome, while aneuploidy is a micro-evolutionary event that results in the gain or loss of individual chromosomes or chromosome arms. Both WGD and aneuploidy can have profound effects on cellular physiology, gene expression and genome stability, and are associated with tumor initiation, progression and drug resistance.

However, the relationship between WGD and aneuploidy is complex and context-dependent. In a new editorial paper, researchers Kavya Prasad and Uri Ben-David from Tel Aviv University discuss a recent study exploring how WGD shapes the aneuploidy landscape of human cancers. Their editorial was published in Oncotarget on April 26, 2023, and entitled, “A balancing act: how whole-genome doubling and aneuploidy interact in human cancer.”

“It is known that tumors that have undergone WGD are more permissive to aneuploidy, but whether WGD also affects aneuploidy patterns has remained an open question.”

The Study

The researchers 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. They found that WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, suggesting that WGD+ tumors are more tolerant to aneuploidy than WGD- tumors. 

The genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, resulting in different co-occurrence and mutual exclusivity patterns. The proportion of whole-chromosome aneuploidy was significantly higher in WGD+ tumors than in WGD- tumors, indicating that different mechanisms of aneuploidy formation are dominant in WGD- and WGD+ tumors. The authors proposed that whole-chromosome missegregation is more prevalent in WGD+ tumors due to increased centrosome amplification and multipolar mitoses.

To validate their findings from the clinical tumor analysis, the authors used human cancer cell lines that reproduced the WGD/aneuploidy interactions observed in vivo. They also induced WGD in human colon cancer cell lines by treating them with a microtubule-stabilizing drug, and followed the evolution of aneuploidy in the isogenic WGD+/WGD- cells under standard or selective conditions. These experiments confirmed that WGD alters the aneuploidy landscape of human cancer cells, and revealed a causal link between WGD and altered aneuploidy patterns.

“We note that these experiments were not powered to assess the associations between specific aneuploidies, which remain to be experimentally validated in future studies.”

Conclusions & Future Studies

In their editorial, the researchers note that their study prompts questions about how different tetraploidization methods affect aneuploidy landscapes. They used cytokinesis failure for cell lines, but processes like cell fusion could impact aneuploidy differently. Further research should explore how selection pressures shape karyotype evolution, considering factors beyond tissue type. Analyzing intra-chromosomal arm-level vs. whole-chromosomal aneuploidies may identify cancer-driving chromosome arms. Overall, this study provides novel insights into how WGD and aneuploidy interact in human cancer, and how this interaction affects tumor evolution. The authors suggest that the interaction between WGD and aneuploidy is a major contributor to tumor heterogeneity, adaptation, and drug resistance, and that targeting this interaction could be a promising therapeutic strategy.

“In summary, our recent study shows that WGD contributes to aneuploidy formation in human tumors in both qualitative and quantitative ways. Hence, we propose that the WGD status of the tumor should be taken into account when examining the tumorigenic role of individual aneuploidies or aneuploidy patterns. In general, WGD should be considered in the study of aneuploidy landscapes in human cancers.”

Click here to read the full editorial in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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