Background & Aims

Lynch syndrome is the most common inherited cause of colorectal cancer (CRC). Contemporary and mutation-specific estimates of CRC-risk in patients undergoing colonoscopy would optimize surveillance strategies. We performed a prospective national cohort study, using data from New Zealand, to assess overall and mutation-specific risk of CRC in patients with Lynch syndrome undergoing surveillance.

Methods

We performed a prospective study of 381 persons with Lynch syndrome in New Zealand (98 with Lynch-syndrome associated variants in MLH1, 159 in MSH2, 103 in MSH6, and 21 in PMS2). Participants were offered annual colonoscopy starting at age 25 y, and those who underwent 2 or more colonoscopies before December 31, 2017 were included in the final analysis. Patients with previous colonic resection, history of CRC or diagnosis of CRC at index colonoscopy were excluded.

Results

Study participants underwent 2061 colonoscopies during 2296 person-y; the median observation-period was 4.43 y and mean-age at enrollment was 43 y. Eighteen patients developed CRC (8 with variants in MLH1, 8 in MSH2, and 2 in MSH6) after a median follow-up period of 6.5 y (range 1–16 y). Eighty-three percent of patients had a surveillance colonoscopy in preceding 24 months before diagnosis of CRC; 94% were diagnosed with stage 0–II CRC and there was no CRC-related mortality. The overall-risk of developing CRC in the 5 y after first surveillance colonoscopy was 2.49% (95% CI, 1.18–5.23); cumulative risks for CRC in patients with Lynch syndrome-associated variants in MLH1, MSH2, or MSH6 by age 70 y were 17.7%, 17.8%, and 8.5%, respectively. Age-adjusted CRC-risk in patients with variants in MSH6 was lower than in MLH1 (hazard ratio, 0.2; 95% CI, 0.04–0.94; P = .02). Of patients with CRC, 33% had an adenomatous polyp resected from same segment in which a colorectal tumor later developed.

Conclusions

The risk of CRC in patients with Lynch syndrome-associated mutations in MSH6 or PMS2 was significantly lower than in patients with mutations in MLH1. Incomplete adenomatous polyp resection might be responsible for one third of surveillance-detected CRCs.

中文翻译：

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MSH6 和 PMS2 突变与监测发现的结直肠癌风险之间的关联。

背景与目标

林奇综合征是结直肠癌 (CRC) 最常见的遗传原因。对接受结肠镜检查的患者的 CRC 风险进行当代和突变特异性估计将优化监测策略。我们使用来自新西兰的数据进行了一项前瞻性国家队列研究，以评估接受监测的 Lynch 综合征患者的 CRC 总体风险和突变特异性风险。

方法

我们对新西兰 381 名 Lynch 综合征患者进行了一项前瞻性研究（MLH1中 98 名 Lynch 综合征相关变异， MSH2中159名， MSH6中 103 名，PMS2中21名）。参与者从 25 岁开始每年接受一次结肠镜检查，在 2017 年 12 月 31 日之前接受过 2 次或以上结肠镜检查的参与者被纳入最终分析。既往结肠切除术、CRC 病史或结肠镜检查诊断为 CRC 的患者被排除在外。

结果

研究参与者在 2296 人年期间接受了 2061 次结肠镜检查；中位观察期为 4.43 岁，入组时平均年龄为 43 岁。18 名患者在 6.5 年（范围 1-16 年）的中位随访期后发展为 CRC（8 例MLH1变异，8例MSH2变异，2例MSH6变异）。83% 的患者在诊断为 CRC 之前的 24 个月内接受了结肠镜检查；94% 被诊断为 0-II 期 CRC，并且没有与 CRC 相关的死亡率。首次监测结肠镜检查后 5 年内发生 CRC 的总体风险为 2.49%（95% CI，1.18-5.23）；具有MLH1、MSH2或MSH6的 Lynch 综合征相关变异患者的 CRC 累积风险到 70 岁时，分别为 17.7%、17.8% 和 8.5%。MSH6变异患者的年龄校正 CRC 风险低于MLH1（风险比，0.2；95% CI，0.04-0.94；P = .02）。在 CRC 患者中，33% 的腺瘤性息肉从同一节段切除，随后发展为结肠直肠肿瘤。

结论

与 Lynch 综合征相关的MSH6或PMS2突变患者发生 CRC 的风险显着低于MLH1突变患者。不完全的腺瘤性息肉切除可能导致三分之一的监测发现的 CRC。