颜林林 (2022-07-14 21:57):
#paper doi:10.1126/science.abl9283 Science, 2022, Substitution mutational signatures in whole-genome–sequenced cancers in the UK population. 这篇今年四月发表在《Science》上的文章,被最新一期《Cancer Cell》所推荐(doi:10.1016/j.ccell.2022.05.011)。这些年做大规模人群做全基因组测序(WGS)的文章并不少见,时至今日仍能发表于顶刊,其创新点及意义,大概还是值得关注和了解下的。本文的入组病例样本来自Genomics England (GEL) 100,000 Genomes Project (100kGP),共计12,222个肿瘤样本(来自11,585位个体)的WGS,在分析得到与肿瘤发生的突变特征后,又在另外两个大型独立队列(来自国际癌症基因组联盟 (ICGC) 的 3001 例原发性癌症和来自 Hartwig 医学基金会的 3417 例转移性癌症)中进行了验证。本文重点关注由WGS分析得到的单碱基替换 (SBS) 和双碱基替换 (DBS) 特征,并建立了一个名为 Signature Fit Multi-Step (FitMS) 的计算框架。该方法用来区分哪些特征是各不同癌种中常见的,而哪些是罕见的、仅出现在特定癌种或器官。而通过对组织特异性特征进行聚类分析,并将其组合起来形成一组参考特征,帮助进行机制和病因的解释。从所解决的问题及方法看,似乎并无特别重大的创新,因此初步推断,之所以能跻身顶刊,与其超大人群及数据量,以及相应的工作量(参见长达94页的补充材料),还是密不可分的。
Substitution mutational signatures in whole-genome-sequenced cancers in the UK population
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Abstract:
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
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