Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75–1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81–1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52–1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Therefore, despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we do not recommend that POEs be incorporated into the clinical guidelines or advice for such carriers.

中文翻译：

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林奇综合征相关癌症的风险是否取决于突变的父母？


携带 DNA 错配修复 (MMR) 基因致病性突变的个体患癌症的风险很高，小型研究表明，这些风险取决于遗传该突变的父母的性别。我们对这种亲本效应（POE）进行了首次大型研究。我们的研究基于结肠癌家族登记处的所有 MMR 基因突变携带者及其亲属，包括 18,226 人。使用针对确定进行调整的隔离分析方法将 POE 估计为风险比 (HR)。 HR = 1 对应于无 POE，HR > 1 对应于母体突变风险较高。对于所有 MMR 基因组合，男性结直肠癌的估计 POE HR 为 1.02（95% 置信区间 (CI) 0.75–1.39，p = 0.9），女性结直肠癌为 1.12（95% CI 0.81–1.54，p = 0.5）子宫内膜癌为 0.84 (95% CI 0.52–1.36, p = 0.5)。每个 MMR 基因的单独结果相似。因此，尽管我们的研究有力，但没有发现任何证据表明 MMR 基因突变携带者的癌症风险取决于突变的亲本。根据目前的证据，我们不建议将 POE 纳入此类携带者的临床指南或建议中。