The hallmark of Lynch syndrome (LS)-associated neoplasia is DNA mismatch repair protein (MMR) deficiency. Recent studies have demonstrated that histologically normal colonic crypts in patients with LS can exhibit deficient MMR expression. The aim of this study was to determine the feasibility of detecting MMR deficient crypts in random colonoscopic biopsies of normal mucosa in patients with and without LS. Forty-nine patients, including 33 with LS, 12 without LS, and 4 with germline MMR gene variants of uncertain significance (VUS), were prospectively and blindly evaluated by immunohistochemistry for MMR deficient crypts within random normal-appearing mucosal biopsies obtained during surveillance colonoscopy. MMR deficient crypts were identified in 70% (23/33) of patients with LS and in no patients without LS (0/12) (p < 0.001). MMR deficient crypts were identified with nearly equal frequency in both LS patients with and without a cancer history and were associated with germline variants in all four MMR genes and EPCAM. MMR deficient crypts were also identified in LS patients with a history of non-colorectal cancer types, including patients with endometrial cancer, skin sebaceous neoplasms, and renal cancer. Two of the four patients with germline MMR gene VUS had MMR deficient crypts. In conclusion, MMR deficient crypts are a specific biomarker of LS and can be identified in random normal mucosal biopsies in LS patients. Evaluation for MMR deficient crypts in colonoscopic biopsies of normal mucosa can help identify LS patients.

中文翻译：

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在随机结肠镜活检中检测到DNA错配修复缺陷的隐窝可鉴定出Lynch综合征患者。

与Lynch综合征（LS）相关的瘤形成的标志是DNA错配修复蛋白（MMR）缺乏。最近的研究表明，LS患者的组织学正常的结肠隐窝可表现出MMR表达不足。这项研究的目的是确定在有或没有LS患者的正常粘膜随机结肠镜活检中检测MMR缺陷隐窝的可行性。对49例患者（包括33例LS，12例无LS和4例具有不确定意义的MMR基因变体）进行了免疫组织化学前瞻性和盲目评估，以监测结肠镜检查中发现的随机正常出现的粘膜活检中的MMR缺陷隐窝。在患有LS的患者中，有70％（23/33）发现了MMR缺陷隐窝，而没有LS的患者中没有发现（0/12）（p <0.001）。EPCAM。在具有非大肠癌类型病史的LS患者（包括子宫内膜癌，皮肤皮脂瘤和肾癌患者）中也发现了MMR缺陷隐窝。生殖系MMR基因VUS的四名患者中有两名患有MMR缺陷隐窝。总之，MMR缺陷隐窝是LS的一种特定生物标志物，可以在LS患者的随机正常黏膜活检中鉴定出来。正常粘膜结肠镜活检中MMR缺陷隐窝的评估可以帮助识别LS患者。