Department of Biology, Emmanuel College, Boston, MA, USA.
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
Mol Biol Evol. 2022 May 3;39(5). doi: 10.1093/molbev/msac084.
Mutational processes in tumors create distinctive patterns of mutations, composed of neutral "passenger" mutations and oncogenic drivers that have quantifiable effects on the proliferation and survival of cancer cell lineages. Increases in proliferation and survival are mediated by natural selection, which can be quantified by comparing the frequency at which we detect substitutions to the frequency at which we expect to detect substitutions assuming neutrality. Most of the variants detectable with whole-exome sequencing in tumors are neutral or nearly neutral in effect, and thus the processes generating the majority of mutations may not be the primary sources of the tumorigenic mutations. Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches-revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies.
肿瘤中的突变过程会产生独特的突变模式，由中性的“乘客”突变和致癌驱动因素组成，这些因素对癌细胞谱系的增殖和存活有可量化的影响。增殖和存活的增加是由自然选择介导的，我们可以通过比较检测到的替换频率与假设中性时预期检测到的替换频率来量化自然选择。在肿瘤中通过全外显子测序检测到的大多数变体在效果上是中性或几乎中性的，因此产生大多数突变的过程可能不是致癌突变的主要来源。在 24 种癌症类型中，我们确定了突变过程对每种致癌变体的贡献，并量化了每个过程对肿瘤发生的贡献程度。我们证明，驱动黑色素瘤和肺癌的变体起源主要归因于分别与紫外线和烟草暴露相关的可预防的外源性突变过程，而胶质瘤和前列腺腺癌中选定变体的起源主要归因于与衰老相关的内源性过程。与病原体暴露和载脂蛋白 B mRNA 编辑酶活性相关的可预防突变，占头颈部、膀胱癌、宫颈癌和乳腺癌中癌症效应的很大一部分。这些归因补充了流行病学方法——揭示了由内源性或外源性、不可预防或可预防过程引起的单核苷酸变体驱动的癌症负担，并且至关重要的是为公共卫生策略提供了信息。
