Background and ObjectivesDisparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non‐colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status.MethodsA retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non‐colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non‐colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex.ResultsOf the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60–75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non‐colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni‐ (IRR = 2.49, 95% confidence interval [CI] = 1.89–3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67–3.01, p = 0.004). This association applied whether or not the non‐colorectal tumor developed before or after the diagnosis of CRC in both uni‐ (IRR = 1.91, 95% CI = 1.28–2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72–3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05–2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63–3.42, p = 0.005), respectively.ConclusionIn this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non‐colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.

中文翻译：

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结直肠癌中偶发的错配修复缺陷会增加非结直肠恶性肿瘤的风险：一项欧洲多中心队列研究

背景和目的尚未对不同散发性致癌途径引起的肿瘤之间的差异进行系统研究。这项回顾性多中心队列研究评估了不同 DNA 错配修复状态的散发性结直肠癌 (CRC) 患者之间发生非结直肠恶性肿瘤的风险差异。方法一项回顾性欧洲多中心队列研究，纳入了 1996 年至 2019 年期间接受治疗的 1706 名 CRC 患者。三个不同的国家。通过免疫组织化学测定错配修复的熟练程度（pMMR）或缺陷（dMMR）。对病例进行肿瘤分析布拉夫V600E突变，以及布拉夫进一步分析突变肿瘤 MLH1 启动子区域的高甲基化状态，以区分散发性病例和遗传性病例。瑞典和芬兰的患者与各自的国家癌症登记处进行匹配。对于捷克队列，对医疗档案进行了彻底审查，以确定 CRC 诊断前后 20 年内是否存在任何非结直肠恶性肿瘤。进行泊松回归分析以确定非结直肠恶性肿瘤的发病率。出于验证目的，计算了瑞典病例的标准化发病率，并根据年龄、年份和性别进行了调整。结果在分析中纳入的 1706 名 CRC 患者中，819 名是女性 [48%]，手术时中位年龄为 67 岁[四分位距: 60–75]，在 188 名患者 (11%) 中发现了散发性 dMMR。与 pMMR 肿瘤患者相比，散发性 dMMR CRC 患者在诊断前后非结直肠恶性肿瘤的发病率比 (IRR) 较高，在单项研究中（IRR = 2.49，95% 置信区间 [CI] = 1.89） 3.31，p= 0.003）和多变量分析（IRR = 2.24，95% CI = 1.67–3.01，p= 0.004）。无论非结直肠肿瘤是在 CRC 诊断之前还是之后发生，该关联均适用于两种单例（IRR = 1.91，95% CI = 1.28-2.98，p= 0.004), (IRR = 2.45, 95% CI = 1.72–3.49,p= 0.004）和多变量分析（IRR = 1.67，95% CI = 1.05–2.65，p= 0.029), (IRR = 2.35, 95% CI = 1.63–3.42,p= 0.005）。 结论 在这项回顾性欧洲多中心队列研究中，散发性 dMMR CRC 患者比 pMMR CRC 患者患非结直肠恶性肿瘤的风险更高。这些发现表明需要进一步研究以确定 dMMR CRC 患者监测策略的需求和设计。