Alcohol consumption is a critical risk factor for multiple types of cancer. A genome can be attacked and acquire numerous somatic mutations in the environment of alcohol exposure. Mutational signature has the capacity illustrating the complex somatic mutation patterns in cancer genome. Recent studies have discovered distinct mutational signatures associating with alcohol consumption in liver and esophageal cancers. However, their prevalence among diverse cancers, impact of genetic background and origin of alcohol-induced mutational signatures remain unclear. By a comprehensive bioinformatics analysis on somatic mutations from patients of four cancer types with drinking information, we identified nine mutational signatures (signatures B–J), among which signature J (similar to COSMIC signature 16) was distinctive to alcohol drinking. Signature J was associated with HNSC, ESCA and LIHC but not PAAD. Interestingly, patients with mutated allele rs1229984 in ADH1B had lower level of signature J while mutated allele rs671 in ALDH2 exhibited higher signature J abundance, suggesting acetaldehyde is one cause of signature J. Intriguingly, somatic mutations of three potential cancer driver genes (TP53, CUL3 and NSD1) were found the critical contributors for increased mutational load of signature J in alcohol consumption patients. Furthermore, signature J was enriched with early accumulated clonal mutations compared to mutations derived from late tumor growth. This study systematically characterized alcohol-related mutational signature and indicated mechanistic insights into the prevalence, origin and gene–environment interaction regarding the risk oncogenic mutations associated with alcohol intake.

中文翻译：

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综合分析揭示了人类癌症中饮酒的不同突变特征及其机制见解。

饮酒是多种癌症的关键危险因素。在酒精暴露的环境中，基因组可以被攻击并获得许多体细胞突变。突变特征能够说明癌症基因组中复杂的体细胞突变模式。最近的研究发现了与肝癌和食道癌饮酒相关的不同突变特征。然而，它们在多种癌症中的流行、遗传背景的影响和酒精诱导的突变特征的起源仍不清楚。通过对具有饮酒信息的四种癌症类型患者的体细胞突变进行综合生物信息学分析，我们确定了九个突变特征（特征 B-J），其中特征 J（类似于 COSMIC 特征 16）与饮酒有关。特征 J 与 HNSC、ESCA 和 LIHC 相关，但与 PAAD 无关。有趣的是，等位基因 rs1229984 突变的患者在ADH1B具有较低水平的特征 J，而ALDH2 中突变的等位基因 rs671表现出较高的特征 J 丰度，表明乙醛是特征 J 的原因之一。有趣的是，三个潜在癌症驱动基因（TP53、CUL3和NSD1）的体细胞突变) 被发现是饮酒患者中特征 J 突变负荷增加的关键因素。此外，与源自晚期肿瘤生长的突变相比，特征 J 富含早期积累的克隆突变。这项研究系统地表征了酒精相关的突变特征，并表明了对与酒精摄入相关的致癌突变风险的流行、起源和基因-环境相互作用的机制见解。