APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma
APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma
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DOI：
10.1038/s41388-018-0657-6
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发表时间：
2019-05-02
期刊：
影响因子：
8
通讯作者：
Townsend, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Cannataro, Vincent L.;Gaffney, Stephen G.;Townsend, Jeffrey P.
最近的研究揭示了癌症体细胞进化的突变特征，以及相关体细胞遗传变异的患病率。在这里，我们估计了正选择的强度，该强度驱动肿瘤中的高频率突变，产生比仅基于突变和中性漂移的预期更高的患病率。我们将这种方法应用于525个头颈部鳞状细胞癌外显子组的样本，通过选择强度产生基因变体的等级排序列表。我们的研究结果说明了计算突变选择强度沿着计算癌症中个体替换的流行程度的互补性：虽然许多最普遍改变的基因被大量选择，但它们对癌症表型的相对重要性与其流行程度和P值不同，一些罕见的变异表现出强阳性选择的证据。此外，我们通过量化突变过程（如APOBEC诱变）对高度选择性突变的贡献程度来扩展我们对效应大小的分析，从而驱动头颈部鳞状细胞癌。我们计算了由APOBEC突变引起的对患者癌症表型贡献最大的置换。最后，我们通过体外生物化学实验证明，APOBEC 3B蛋白可以脱氨基的胞嘧啶碱基在两个网站，其突变状态受到高净实现选择强度-PIK 3CA E545 K和E542 K。通过量化突变的影响，我们加深了对头颈部鳞状细胞癌致癌作用的分子理解。
Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities-PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.