背景林奇综合征 (LS) 是一种遗传性癌症易感综合征，由影响 DNA 错配修复 (MMR) 基因 MLH1、MSH2、MSH6 和 PMS2 的遗传变异引起。LS 的癌症风险是根据个人或家族癌症史确定的个体队列来估计的，其中使用全外显子组序列在 454-756 名英国生物银行 (UKB) 参与者中鉴定出 830 个由 InSiGHT 分类的致病性或可能致病性 (path_MMR) MMR 基因变异携带者。 Nelson-Aalen 生存分析用于估计结直肠癌、子宫内膜癌和乳腺癌 (BC) 的累积发病率。与非携带者相比，path_MMR 携带者到 70 岁时结直肠癌和子宫内膜癌 (EC) 的累积发病率升高（结直肠癌：11.8） %（95% 置信区间 (CI)：9.5% 至 14.6%）对比 1.7%（95% CI：1.6% 至 1.7%），子宫内膜：13.4%（95% CI：10.2% 至 17.6%）对比 1.0%（ 95% CI：0.9% 至 1.0%）），但这种增加的幅度因基因而异。与非携带者相比，path_MMR 携带者在 70 岁时的累积 BC 发病率并未升高（8.9%（95% CI：6.3% 至 12.4%）与 7.5%（95% CI：7.4% 至 7.6%））。 UKB 的累积癌症发病率估计与前瞻性林奇综合征数据库中所有基因和癌症的估计相似，但没有证据表明 UKB 致病性 PMS2 变异携带者的 EC 风险升高。这些结果支持提供任何路径_MMR 的偶然识别携带者监测以管理结直肠癌风险。顺便说一句，已确定的 MLH1、MSH2 和 MSH6 致病变异携带者也将受益于降低 EC 风险的干预措施。结果表明 BC 不是 LS 相关癌症。© 作者（或其雇主）2024。CC BY 允许重复使用。由英国医学杂志出版。

BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in path_MMR carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in path_MMR carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic PMS2 variants in UKB.These results support offering incidentally identified carriers of any path_MMR surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in MLH1, MSH2 and MSH6 would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.