Clinicopathological and molecular characterization of deficient mismatch repair colorectal cancer
Clinicopathological and molecular characterization of deficient mismatch repair colorectal cancer
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DOI：
10.1016/j.humpath.2022.09.005
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发表时间：
2022-10-19
期刊：
影响因子：
3.3
通讯作者：
Muto, Manabu
中科院分区：
文献类型：
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作者：
Yamada, Atsushi;Yamamoto, Yoshihiro;Muto, Manabu
显示缺陷错配修复（dMMR）的肿瘤占结肠直肠癌（crc）的12%-15%，但其特征尚未完全阐明。本研究的目的是根据临床病理表现和分子改变来表征dMMR crc。对错配修复（MMR）蛋白进行免疫染色以确定MMR状态，然后通过下一代测序分析dMMR肿瘤中MLH1启动子甲基化和25个参与结直肠癌发生的基因的遗传变异。对癌前病变的共存进行组织学评估，以表征前体的类型。492例crc中，免疫组化示34个dMMR肿瘤。在dMMR crc中，MLH1甲基化阳性肿瘤25例，BRAF V600E变异阳性肿瘤16例，KRAS变异阳性肿瘤7例。MLH1甲基化阳性与BRAF V600E、年龄和右侧肿瘤位置相关。MLH1甲基化BRAF/KRAS野生型肿瘤的不同之处在于，所有5种肿瘤都具有不依赖配体的WNT信号基因变异，包括APC、AXIN2和CTNNB1。在10例出现癌前病变的dMMR crc中，4例BRAF变异体阳性、1例KRAS变异体阳性和2例BRAF/KRAS野生型MLH1甲基化肿瘤与锯齿状病变共存，而1例MLH1甲基化BRAF/KRAS野生型肿瘤和2例MLH1未甲基化肿瘤与常规腺瘤共存。本研究基于分子改变，包括MLH1甲基化和BRAF、KRAS和不依赖配体的WNT信号基因的变异，表征了dMMR crc的不同亚群。包括锯齿状病变和常规腺瘤在内的不同前体病变的存在进一步说明了在dMMR crc的发展中参与了异质性的致癌途径。(c) 2022爱思唯尔公司版权所有。
Tumors demonstrating deficient mismatch repair (dMMR) account for 12%-15% of colo-rectal cancers (CRCs), but their characteristics have not been fully elucidated. The aim of this study was to characterize dMMR CRCs in terms of clinicopathological findings and molecular alterations. Immunostaining for mismatch repair (MMR) proteins was performed to determine MMR status, and then MLH1 promoter methylation and genetic variants of 25 genes involved in colorectal carcinogen-esis were analyzed by next-generation sequencing in dMMR tumors. Coexistence of precancerous le-sions was histologically evaluated to characterize the type of precursors. Immunohistochemistry revealed 34 dMMR tumors in 492 CRCs. Among dMMR CRCs, there were 25 MLH1 methylation-positive, 16 BRAF V600E variant-positive, and 7 KRAS variant-positive tumors. Positive MLH1 methylation was associated with BRAF V600E, older age, and right-side tumor location. MLH1 meth-ylated BRAF/KRAS wild-type tumors were distinct in that all 5 tumors possessed variants in ligand-independent WNT signaling genes including APC, AXIN2, and CTNNB1. Among 10 dMMR CRCs that presented with precancerous lesions, 4 BRAF variant-positive, 1 KRAS variant-positive, and 2 BRAF/ KRAS wild-type MLH1 methylated tumors coexisted with serrated lesions, whereas 1 MLH1 methyl-ated BRAF/KRAS wild-type tumor and 2 MLH1 unmethylated tumors accompanied conventional ad-enomas. The present study characterized distinct subgroups of dMMR CRCs based on molecular alterations including MLH1 methylation and variants in BRAF, KRAS, and ligand-independent WNT signaling genes. The existence of distinct precursor lesions including serrated lesion and conventional adenoma further illustrates the involvement of heterogeneous carcinogenetic pathways in the develop-ment of dMMR CRCs.(c) 2022 Elsevier Inc. All rights reserved.