利用英国生物库（UK Biobank）携带者的Lynch综合征变异体癌症风险估算

Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

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JOURNAL OF MEDICAL GENETICS

影响因子:3.7

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

DOI: 10.1136/jmg-2023-109791

摘要

背景：Lynch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）突变引起。LS患者的癌症风险通常通过个体或家族癌症史的队列估算，可能会导致估算值偏高。在英国生物库（UK Biobank）中，利用全外显子组测序鉴定了454,756名参与者中的830名致病或可能致病（path_MMR）MMR基因变异携带者。采用Nelson-Aalen生存分析方法，估算结直肠癌、子宫内膜癌和乳腺癌的累计发病率。结果显示，至70岁，path_MMR携带者的结直肠癌和子宫内膜癌的累计发病率较非携带者显著升高（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%）；子宫内膜癌：13.4%（95% CI：10.2%至17.6%）对比1.0%（95% CI：0.9%至1.0%）），但不同基因间差异显著。至70岁的乳腺癌累计发病率在携带者中未显著升高（8.9%（95% CI：6.3%至12.4%）对比7.5%（95% CI：7.4%至7.6%））。UKB的累计癌症发病率估算与前瞻性Lynch综合征数据库的估算基本一致，除在携带PMS2致病变异的个体中未观察到子宫内膜癌风险升高。这些结果支持为偶然发现的任何path_MMR携带者提供监测措施以管理结直肠癌风险。携带MLH1、MSH2和MSH6致病变异的个体也应接受干预以降低子宫内膜癌风险。结果表明，乳腺癌并非LS相关癌症。

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.