伦敦大学癌症研究所Nicholas McGranahan团队近日取得一项新成果。他们发现全基因组加倍（WGD）与恶性肿瘤进化过程中有害突变累积的相互作用。相关论文于2020年3月5日在线发表在《自然-遗传学》杂志上。

研究人员将进化模拟与癌症测序数据分析相结合，以探索癌症进化过程中的WGD。模拟研究表明，WGD可以选择性减轻棘轮状、不可逆、有害体细胞突变的积累，只要它们以足够高的频率发生。

与此相一致，研究人员观察到WGD在杂合缺失的肿瘤类型中富集，包括肺鳞状细胞癌和三阴性乳腺癌；并且研究人员还发现了在WGD之前而不是之后，针对必需基因纯合缺失负选择的证据。

最后，该研究证明了杂合缺失和突变时序可以用来鉴定新的肿瘤抑制基因，并可获得已知癌症基因的更深层特征。

据悉，全基因组加倍是癌症中的常见事件，这涉及整个染色体补体的加倍。尽管其发生和预后相关，但尚未研究WGD在癌症中的进化选择压力。

附：英文原文

Title: Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution

Author: Saioa Lpez, Emilia L. Lim, Stuart Horswell, Kerstin Haase, Ariana Huebner, Michelle Dietzen, Thanos P. Mourikis, Thomas B. K. Watkins, Andrew Rowan, Sally M. Dewhurst, Nicolai J. Birkbak, Gareth A. Wilson, Peter Van Loo, Mariam Jamal-Hanjani, Charles Swanton, Nicholas McGranahan

Issue&Volume: 2020-03-05

Abstract: Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.

DOI: 10.1038/s41588-020-0584-7

Source: https://www.nature.com/articles/s41588-020-0584-7