BACKGROUND & AIMS Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS Risk of advanced adenoma in 10 y was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P<.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 y (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P=.001 and P=.003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P=.015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P=.002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

中文翻译：

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MLH1，MSH2和MSH6的致病性变异与大肠腺瘤和肿瘤风险以及Lynch综合征患者的体细胞突变的关联。

背景与目的林奇综合征是由DNA错配修复（MMR）基因的变异引起的，并且与大肠癌（CRC）的风险增加相关。在Lynch综合征患者中，CRC可以通过不同途径发展。我们在国际患者队列中研究了MMR基因中与Lynch综合征相关的变异与腺瘤和CRC的风险以及肿瘤中APC和CTNNB1的体细胞突变之间的关联。方法我们结合了3项研究的临床和分子数据。我们从德国，荷兰和芬兰的2747名Lynch综合征患者中获得了与MLH1，MSH2或MSH6变异相关的临床数据，这些患者至少接受了2次结肠镜检查，随访中位时间为7.8年，以发现腺瘤或CRC。我们对48个大肠肿瘤（来自16例MLH1突变的患者，29例MSH2突变的患者和3例MSH6突变的患者）进行了DNA序列分析，以分析APC和CTNNB1的体细胞突变。结果MSH2病原体变异患者在10年内发生晚期腺瘤的风险为17.8％，而MLH1为7.7％（P <.001）。MLH1或MSH2的致病性变异患者发生CRC的比例高于MSH6的致病性变异患者（4.7％）的10年（11.3％和11.4％）（MLH1和MSH2 vs MSH6的P = .001和P = .003 ， 分别）。在MSH2中有致病变异的患者中，有75％的肿瘤中发现了APC的体细胞突变，而MLH1中则有11％（P = .015）。在MLH1中有致病性变异的患者中，有50％的肿瘤中发现了CTNNB1的体细胞突变，而MSH2中则为7％（P = .002）。MSH6中具有致病性变异的3种肿瘤均未在CTNNB1中发生突变，但在APC中均发生了突变。结论在对来自3个国家的Lynch综合征患者的临床和DNA序列数据进行的分析中，我们将MMR基因的致病变异与腺瘤和CRC的风险以及结直肠肿瘤中APC和CTNNB1的体细胞突变相关联。如果这些发现得到证实，则可以根据MMR基因变异对监测指南进行调整。