英国弗朗西斯·克里克研究所Peter Van Loo、Jonas Demeulemeester等研究人员合作发现，癌症基因组中的双等位突变可揭示局部突变的决定因素。2022年2月10日，《自然—遗传学》杂志在线发表了这项成果。

研究人员在泛癌全基因组分析研究的559个（21%）批量测序样本中发现了18,295个双等位突变，即同一碱基在两个亲本上独立突变。双等位突变揭示了E26转化特异性（ETS）和活化T细胞核因子（NFAT）结合位点的紫外线损伤热点，以及POLE突变体和其他癌症中的高变异模体。研究人员制定了变体查询的建议，并提供了建模和检测双等位突变的框架。这些结果突出了对突变率和肿瘤演化的准确模型的需求，以及从测序数据中推断它们。

据悉，分子进化的无限位点模型认为，基因组中的每个位置最多发生一次突变。通过限制可能的突变历史、单倍型和等位基因的数量，它构成了肿瘤系统学分析的基石，并且在调用、分期和解释变体或研究整个突变图谱时经常提及。

附：英文原文

Title: Biallelic mutations in cancer genomes reveal local mutational determinants

Author: Demeulemeester, Jonas, Dentro, Stefan C., Gerstung, Moritz, Van Loo, Peter

Issue&Volume: 2022-02-10

Abstract: The infinite sites model of molecular evolution posits that every position in the genome is mutated at most once1. By restricting the number of possible mutation histories, haplotypes and alleles, it forms a cornerstone of tumor phylogenetic analysis2 and is often implied when calling, phasing and interpreting variants3,4 or studying the mutational landscape as a whole5. Here we identify 18,295 biallelic mutations, where the same base is mutated independently on both parental copies, in 559 (21%) bulk sequencing samples from the Pan-Cancer Analysis of Whole Genomes study. Biallelic mutations reveal ultraviolet light damage hotspots at E26 transformation-specific (ETS) and nuclear factor of activated T cells (NFAT) binding sites, and hypermutable motifs in POLE-mutant and other cancers. We formulate recommendations for variant calling and provide frameworks to model and detect biallelic mutations. These results highlight the need for accurate models of mutation rates and tumor evolution, as well as their inference from sequencing data. Common mutational analyses assume that every base in the genome can only mutate once. Here, the authors report multiple violations of this infinite sites model in whole-genome data across a range of tumor types.

DOI: 10.1038/s41588-021-01005-8

Source: https://www.nature.com/articles/s41588-021-01005-8