MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas.
MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas.
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DOI：
10.3802/jgo.2021.32.e79
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发表时间：
2021-11
影响因子：
3.9
通讯作者：
Terada Y
中科院分区：
文献类型：
--
作者：
Kaneko E;Sato N;Sugawara T;Noto A;Takahashi K;Makino K;Terada Y
已经报道了抗PD-1抗体对错配修复缺陷（MMR-D）相关癌症的抗肿瘤作用。MMR-D在大约20%-30%的子宫内膜癌（EC）中发现，并且经常由于MLH 1启动子高甲基化（MLH 1-PHM）而发生。根据Lynch综合征（LS）的分子筛选，对MLH 1-PHM EC进行了分类，但很少有详细的报道。本研究的目的是阐明EC与MLH 1-PHM的临床特征。对2003年至2018年在我们大学医院治疗的527例EC的标本进行了MMR蛋白（MLH 1，MSH 2，MSH 6和PMS 2）的免疫组化。MLH 1甲基化分析添加到MLH 1/PMS 2丢失的病例中。EC分类如下：保留MMR蛋白的病例为“MMR-熟练”; MLH 1/PMS 2缺失和MLH 1-PHM的病例为“met-EC”;其他MMR蛋白缺失和MLH 1/PMS 2缺失而没有MLH 1-PHM的病例为“疑似LS”。分析各组患者的临床特征及远期预后。因此，419例（79.5%）、65例（12.3%）和43例（8.2%）病例分别被归类为“MMR-熟练”、“疑似LS”和“met-EC”。值得注意的是，与其他组相比，“met-EC”具有较低的1级肿瘤比例（37.5%）和较高的III/IV期肿瘤比例（37.2%）。在所有病例中，“met-EC”的总体生存期和无进展生存期均显著差于“疑似LS”。在MMR-D的EC中，“met-EC”是比“疑似LS”预后更差的亚组。“Met-ECs”将是抗PD-1抗体治疗的主要靶点，其临床敏感性应单独验证。
The antitumor effects of anti-PD-1 antibody against mismatch repair deficiency (MMR-D)-associated cancers have been reported. MMR-D is found in approximately 20%–30% of endometrial carcinomas (ECs) and frequently occurs due to MLH1 promoter hypermethylation (MLH1-PHM). ECs with MLH1-PHM are classified according to the molecular screening of Lynch syndrome (LS), but few detailed reports are available. The purpose of this study was to clarify the clinical features of EC with MLH1-PHM. Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed on specimens from 527 ECs treated at our university hospital from 2003 to 2018. MLH1 methylation analysis was added to cases with MLH1/PMS2 loss. ECs were classified as follows: cases that retained MMR proteins as “MMR-proficient;” cases with MLH1/PMS2 loss and MLH1-PHM as “met-EC;” and cases with other MMR protein loss and MLH1/PMS2 loss without MLH1-PHM as “suspected-LS.” The clinical features, including long-term prognosis, of each group, were analyzed. Accordingly, 419 (79.5%), 65 (12.3%), and 43 (8.2%) cases were categorized as “MMR-proficient,” “suspected-LS,” and “met-EC,” respectively. Significantly, “met-EC” had a lower proportion of grade 1 tumors (37.5%) and a higher proportion of stage III/IV tumors (37.2%) than the other groups. The overall and progression-free survival of “met-EC” were significantly worse than those of “suspected-LS” in all cases. In ECs with MMR-D, “met-ECs” were a subgroup with a poorer prognosis than “suspected-LS.” “Met-ECs” would be the main target for anti-PD-1 antibody treatment, and its clinical susceptibility should be verified individually.