估计英国生物库中Lynch综合征变体携带者的癌症风险
Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank
影响因子:3.70000
分区:医学2区 / 遗传学2区
发表日期:2024 Aug 29
作者:
Eilidh Fummey, Pau Navarro, John-Paul Plazzer, Ian M Frayling, Sara Knott, Albert Tenesa
摘要
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在454 756 UK Biobank（UKB）参与者中使用全外观序列鉴定了由洞察力分类的基因变体。纳尔逊 - 亚烯的生存分析用于估计结直肠癌，子宫内膜和乳腺癌（BC）的累积发生率。与70岁的结直肠癌和子宫内膜癌（EC）的肿瘤发生率升高，PATH_MMR携带者在非携带者中升高了（95％的置信度：95％的置信区：9.5％ves 14％）：9.5％（95％）：9.5％（95％）：9.5％（9.5％）。 CI：1.6％至1.7％），子宫内膜：13.4％（95％CI：10.2％至17.6％）vs 1.0％（95％CI：0.9％至1.0％）），但基因之间的幅度增加了。与非接管人相比，PATH_MMR载体的累积BC发病率并未升高（8.9％（95％CI：6.3％至12.4％）vs 7.5％（95％CI：7.4％至7.6％））。 UKB的累积癌症发生率估计与所有基因和癌症的前瞻性Lynch综合征数据库的估计值相似，除了没有证据表明在UKB的致病PMS2变体载体中，EC风险升高。这些结果支持这些结果提供的任何Path_mmr勘测的载体可用于管理结型癌症。 MLH1，MSH2和MSH6中偶然发现的致病变异载体也将受益于降低EC风险的干预措施。结果表明，BC不是与LS相关的癌症。
Abstract
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.