摘要

Lynch syndrome is most often caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, or MSH6) or EPCAM and is associated with a significantly increased risk of endometrial cancer in affected women. Although universal screening of endometrial cancer for Lynch syndrome is becoming increasingly common by various algorithms using MMR immunohistochemistry and/or microsatellite instability testing by PCR, establishing the diagnosis of Lynch syndrome can be still challenging. MMR-deficient nonneoplastic colonic crypts have been recently described in Lynch syndrome patients with colorectal carcinoma, and have been proposed to be a novel indicator of Lynch syndrome. Presence of MMR-deficient nonneoplastic endometrial glands have not yet been systematically evaluated in Lynch syndrome patients. We performed MMR protein immunohistochemistry in prophylactic hysterectomies and endometrial curettings/biopsies from 27 patients with known Lynch syndrome confirmed by germline mutation analysis. A total of 56 control benign endometrial tissues were also analyzed, and included benign endometrium adjacent to MMR-deficient sporadic (MLH1 promoter hypermethylated) endometrial carcinoma (n = 9), adjacent to MMR-intact sporadic endometrial carcinoma (n = 27), and normal endometrium from hysterectomies performed for benign disease (n = 20). MMR protein deficient nonneoplastic endometrial glands were identified in 70% (19 of 27) of Lynch syndrome patients. In all 19 cases the MMR protein loss was specific for the patients' known germline mutation. None of the control cases showed loss of MMR protein expression in nonneoplastic endometrium. Our findings suggest that MMR-deficient nonneoplastic endometrial glands may be a unique, specific marker of Lynch syndrome, and may provide an important insight into the pathogenesis of Lynch syndrome-associated endometrial cancer. Evaluation of MMR protein expression of benign background endometrium in endometrial cancer patients may be further explored as a possible useful addition to the Lynch syndrome screening algorithm.

译文

Lynch 综合征最常由四个 DNA 错配修复 (MMR) 基因 (MLH1 、 PMS2 、 MSH2 或 MSH6) 之一的种系突变引起或者 EPCAM，并且与受影响女性患子宫内膜癌的风险显著增加相关。尽管通过使用 MMR 免疫组织化学和/或 PCR 的微卫星不稳定性检测的各种算法，子宫内膜癌 Lynch 综合征的通用筛查变得越来越普遍，但建立 Lynch 综合征的诊断仍然具有挑战性。MMR 缺陷的非肿瘤性结肠隐窝最近在 Lynch 综合征患者的结直肠癌中被描述，并被提出作为 Lynch 综合征的新指标。在 Lynch 综合征患者中，尚未系统评估 MMR 缺陷的非肿瘤性子宫内膜腺的存在。我们对 27 例通过生殖系突变分析证实的已知 Lynch 综合征患者进行了预防性子宫切除术和子宫内膜刮除术/活检，并进行了 MMR 蛋白免疫组织化学。同时分析了 56 例对照良性子宫内膜组织，包括与 MMR 缺陷散发性 (MLH1 启动子高甲基化) 子宫内膜癌 (n =-9) 相邻的良性子宫内膜, 邻近 MMR 完整的散发性子宫内膜癌 (n =-27)，和良性疾病子宫切除术的正常子宫内膜 (n =-20)。MMR 蛋白缺陷的非肿瘤性子宫内膜腺在 70% (27 例中的 19 例) 的 Lynch 综合征患者中被确认。在所有 19 个病例中，MMR 蛋白丢失是针对患者已知的生殖系突变的。在非肿瘤性子宫内膜中，无一例对照病例显示 MMR 蛋白表达缺失。我们的研究结果表明，MMR 缺陷的非肿瘤性子宫内膜腺可能是 Lynch 综合征的一种独特的特异性标记，并可能为 Lynch 综合征相关的子宫内膜癌的发病机制提供重要的见解。对子宫内膜癌患者良性背景子宫内膜 MMR 蛋白表达的评估可能会进一步探索，作为 Lynch 综合征筛查算法的一个可能的有用补充。