Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma
Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma
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DOI：
10.1038/s41379-020-0501-8
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发表时间：
2020-02-14
期刊：
影响因子：
7.5
通讯作者：
Butzow, Ralf
中科院分区：
文献类型：
--
作者：
Pasanen, Annukka;Loukovaara, Mikko;Butzow, Ralf
DNA错配修复(MMR)缺陷型子宫内膜癌(EC)的发病机制是由MMR基因(MLH1、PMS2、MSH2或MSH6)的甲基化失活或突变频率较低所致。本研究评估了甲基化相关的和非甲基化的MMR缺陷的子宫内膜样内皮细胞的预后和临床病理差异。我们进行了MMR免疫组织化学和甲基化特异性多重连接依赖的探针扩增，将682个未选择的子宫内膜样内皮细胞分为MMR熟练(MMRp，n=438)和MMR缺陷(MMRD，n=244)，后者细分为甲基化(MMRD Met)和非甲基化肿瘤。MMR蛋白表达缺失率为35.8%，其中MLH1+PMS2为29.8%，PMS2为0.9%，MSH2+MSH6为1.3%，MSH6为2.8%，多发性异常为0.9%。在244例MMRD病例中，76%与甲基化有关。MMR缺陷与高龄、高分化(G3)、晚期(II-IV)、肿瘤体积较大、肿瘤浸润性淋巴细胞丰富、免疫细胞PD-L1阳性及综合评分阳性、野生型P53、L1CAM阴性、ARID1A缺失、辅助治疗类型有关。MMRD-Met表型与年龄和较大的肿瘤大小相关，并预测整个队列中疾病特异性生存率的降低。在MMRD亚组中，单因素分析显示疾病特异性存活率与疾病II-IV期、高级别(G3)、深肌层侵犯、淋巴管侵犯、ER阴性和L1CAM阳性有关。综上所述，MMR甲基化与子宫内膜样癌的临床病理特征相关，MMRD-Met表型预示着较低的疾病特异性生存率。MMR缺陷，而不是MLH1甲基化状态，与T细胞炎症和PD-L1表达相关。
The pathogenesis of DNA mismatch repair (MMR)-deficient endometrial carcinoma (EC) is driven by inactivating methylation or less frequently mutation of an MMR gene (MLH1, PMS2, MSH2, or MSH6). This study evaluated the prognostic and clinicopathologic differences between methylation-linked and nonmethylated MMR-deficient endometrioid ECs. We performed MMR immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification, and classified 682 unselected endometrioid ECs as MMR proficient (MMRp, n = 438) and MMR deficient (MMRd, n = 244), with the latter subcategorized as methylated (MMRd Met) and nonmethylated tumors. Loss of MMR protein expression was detected in 35.8% of the tumors as follows: MLH1 + PMS2 in 29.8%, PMS2 in 0.9%, MSH2 + MSH6 in 1.3%, MSH6 in 2.8%, and multiple abnormalities in 0.9%. Of the 244 MMRd cases, 76% were methylation-linked. MMR deficiency was associated with older age, high grade of differentiation (G3), advanced stage (II-IV), larger tumor size, abundant tumor-infiltrating lymphocytes, PD-L1 positivity in immune cells and combined positive score, wild-type p53, negative L1CAM, ARID1A loss, and type of adjuvant therapy. MMRd-Met phenotype correlated with older age and larger tumor size, and predicted diminished disease-specific survival in the whole cohort. In the MMRd subgroup, univariate analysis demonstrated an association between disease-specific survival and disease stage II-IV, high grade (G3), deep myometrial invasion, lymphovascular invasion, ER negativity, and L1CAM positivity. In conclusion, MMR methylation profile correlates with clinicopathologic characteristics of endometrioid EC, and MMRd-Met phenotype predicts lower disease-specific survival. MMR deficiency, but not MLH1 methylation status, correlates with T-cell inflammation and PD-L1 expression.