Background We examined whether the association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of defective MMR (dMMR)-related tumor mutational signatures (TMSs). Methods We used data from 227,916 men and women who participated in the Nurses’ Health Study (1980-2016), the Nurses’ Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016). Dietary data was collected every 4 years through validated food frequency questionnaires. Relative contributions of two dMMR-related TMSs (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC cases. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the TMSs. All statistical tests were 2-sided. Results We documented 825 incident CRC cases with available TMS data over 26-36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (P-heterogeneitytrend = 0.02) compared to tumors with lower contributions of this TMS. Compared with nondrinkers, drinkers with ≥15 g/d of alcohol had a high risk of c-dMMRb/SBS26-high CRC [multivariable-adjusted HR: 2.43 (95% CI: 1.55-3.82)], but not c-dMMRb/SBS26-low CRC [0.86 (95% CI: 0.57-1.28)] or c-dMMRb/SBS26-moderate CRC [1.14 (95% CI: 0.76-1.71)]. No significant differential associations were observed for c-dMMRa/SBS15 (P-heterogeneitytrend = 0.41). Conclusions High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.

中文翻译：

---

根据 DNA 错配修复缺陷的突变特征对酒精和结直肠癌风险进行了细分

背景我们检查了对于缺陷 MMR (dMMR) 相关肿瘤突变特征 (TMS) 贡献较高的肿瘤，饮酒与 CRC 发病率之间的关联是否更强。方法 我们使用了参加护士健康研究 (1980-2016)、护士健康研究 II (1991-2017) 和卫生专业人员随访研究 (1986-2016) 的 227,916 名男性和女性的数据。通过经过验证的食物频率调查问卷每 4 年收集一次饮食数据。使用事件 CRC 病例子集中的全外显子组测序数据对两种 dMMR 相关 TMS（c-dMMRa/SBS15 和 c-dMMRb/SBS26）的相对贡献进行量化。根据 TMS 的不同贡献，使用重复法 Cox 比例风险回归模型评估饮酒与 CRC 亚型风险之间的关联。所有统计检验都是双面的。结果 我们记录了 825 起 CRC 病例，并提供了 26-36 年随访期间可用的 TMS 数据。与 TMS 贡献较低的肿瘤相比，对于 c-dMMRb/SBS26 贡献较高的肿瘤（P-异质性趋势 = 0.02），饮酒与 CRC 发病率之间的关联更强。与不饮酒者相比，每天饮酒量≥15 g的饮酒者患c-dMMRb/SBS26高CRC的风险较高[多变量调整HR：2.43（95% CI：1.55-3.82）]，但c-dMMRb/则不然SBS26-低 CRC [0.86 (95% CI: 0.57-1.28)] 或 c-dMMRb/SBS26-中 CRC [1.14 (95% CI: 0.76-1.71)]。 c-dMMRa/SBS15 没有观察到显着的差异关联（P-异质性趋势 = 0.41）。结论 大量饮酒与 c-dMMRb/SBS26 贡献较高的 CRC 发病率增加相关，表明饮酒可能通过 DNA 错配修复途径参与结直肠癌的发生。