Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution.,Nature Genetics

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Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-03-05 , DOI: 10.1038/s41588-020-0584-7
Saioa López _{1,

2} , Emilia L Lim _{2,

3} , Stuart Horswell ₄ , Kerstin Haase ₅ , Ariana Huebner _{1,

2,

3} , Michelle Dietzen _{1,

2,

3} , Thanos P Mourikis _{1,

2} , Thomas B K Watkins ₃ , Andrew Rowan ₃ , Sally M Dewhurst ₆ , Nicolai J Birkbak _{3,

7} , Gareth A Wilson ₃ , Peter Van Loo _{5,

8} , Mariam Jamal-Hanjani _{2,

9} , , Charles Swanton _{2,

3} , Nicholas McGranahan _{1,

2}

Affiliation

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.

中文翻译：

全基因组加倍与癌症进化中有害改变的积累之间的相互作用。

全基因组加倍（WGD）是癌症中常见的事件，涉及整个染色体补体的加倍。然而，尽管 WGD 普遍存在并且与预后相关，但癌症中 WGD 的进化选择压力尚未得到研究。在这里，我们将进化模拟与癌症测序数据分析结合起来，探索癌症进化过程中的全基因组测序。模拟表明，可以选择 WGD 来减轻不可逆的、棘轮状的有害体细胞改变的积累，只要它们以足够高的速度发生。与此一致的是，我们观察到杂合性广泛丧失的肿瘤类型（包括肺鳞状细胞癌和三阴性乳腺癌）中全基因组检测（WGD）富集，并且我们发现了针对必需基因纯合性丧失之前而非之后的阴性选择的证据。工作组。最后，我们证明可以利用杂合性的丧失和突变的时间解剖来识别新的肿瘤抑制基因并获得已知癌症基因的更深入的表征。

更新日期：2020-04-24

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