高级检索
中华病理学杂志
期刊首页
过刊列表
高级检索
稿件发表
• 论著 •
ENGLISH ABSTRACT
PMS2和MSH6双抗体检测在肿瘤错配修复缺陷筛查中的运用
王朝姗
张标
孙琦
杨军
崔晓宾
吴鸿雁
作者及单位信息
·
DOI： 10.3760/cma.j.cn112151-20240531-00354
Application of PMS2 and MSH6 double-antibody detection in screening of mismatch repair deficient tumors
Wang Chaoshan
Zhang Biao
Sun Qi
Yang Jun
Cui Xiaobin
Wu Hongyan
Authors Info & Affiliations
Wang Chaoshan
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Zhang Biao
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Sun Qi
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Yang Jun
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Cui Xiaobin
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Wu Hongyan
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
·
DOI： 10.3760/cma.j.cn112151-20240531-00354
276
71
0
0
0
0
PDF下载
APP内阅读
摘要

目的探讨检测2个标志物PMS2、MSH6（以下简称2-MMR）的免疫组织化学结果能否替代4个标志物MLH1、PMS2、MSH2、MSH6（以下简称4-MMR）来揭示该样本是否有错配修复缺陷（mismatch repair deficient，dMMR）。

方法对南京大学医学院附属鼓楼医院2018年3月至2023年3月诊断的7 867例胃癌、结直肠癌、子宫内膜癌及其他疾病的免疫组织化学数据进行回顾性分析汇总，对比2-MMR与4-MMR的一致性。并且对特殊表型病例进行微卫星不稳定性（MSI）检测和二代测序检测。

结果在胃癌、结直肠癌、子宫内膜癌和其他疾病中2-MMR与4-MMR检测的一致性Cohen κ值分别为0.88、0.99、0.88和1.00，总体一致性为0.97，灵敏度为99.6%，特异度为100.0%。2-MMR与4-MMR检测均能体现不同临床病理特征之间的差异。7 867例患者中出现24例MMR特殊表型病例（0.3%，24/7 867），研究选取其中6例进行MSI和二代测序分子检测，MSI检测结果均为高频MSI，二代测序检测发现其中5例有MMR相关基因突变，1例有POLE p.S297F突变。

结论2-MMR与4-MMR免疫组织化学检测相比，具有高一致性、特异度和灵敏度，特殊表型病例占比极低，因此在筛查dMMR方面可考虑采用2-MMR取代4-MMR。

DNA错配修复;免疫组织化学;微卫星不稳定性;PMS2;MSH6
ABSTRACT

ObjectiveTo investigate whether the immunohistochemical results of two markers PMS2 and MSH6 (2-MMR) could replace the four markers MLH1, PMS2, MSH2 and MSH6 (4-MMR) to detect mismatch repair deficient (dMMR) cancers.

MethodsA retrospective analysis was conducted with summary of immunohistochemical data from 7 867 cases of gastric cancer, colorectal cancer, endometrial cancer, and other diseases in the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China, from March 2018 to March 2023. The consistency of 2-MMR and 4-MMR results was examined. Microsatellite instability (MSI) and next-generation sequencing (NGS) were performed in patients with specific phenotypes.

ResultsThe Cohen κ values of 2-MMR and 4-MMR in gastric cancer, colorectal cancer, endometrial cancer and other diseases were 0.88, 0.99, 0.88 and 1.00, respectively. The overall consistency, sensitivity and specificity were 0.97, 99.6%, and 100.0%, respectively. Both 2-MMR and 4-MMR could detect the difference between various clinicopathological features. 24 (0.3%) of the 7 867 patients were found to have a special phenotype of MMR, and 6 of them were selected for MSI and NGS molecular testing. MSI analysis showed MSI-H in all cases, while NGS found that 5 of them had MMR-related gene mutations and 1 had POLE p.S297F mutation.

ConclusionsCompared with 4-MMR, 2-MMR has high consistency, specificity and sensitivity. The cases with special phenotype only account for extremely low proportion. Therefore, 4-MMR may be replaced with 2-MMR in dMMR screening.

DNA mismatch repair;Immunohistochemistry;Microsatellite instability;PMS2;MSH6
Wu Hongyan, Email: mocdef.yabylgjn8281nayiad
Copyright by Chinese Medical Association
No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission.
All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.
引用本文

王朝姗,张标,孙琦,等. PMS2和MSH6双抗体检测在肿瘤错配修复缺陷筛查中的运用[J]. 中华病理学杂志,2025,54(02)：126-134.

DOI:10.3760/cma.j.cn112151-20240531-00354

PERMISSIONS

Request permissions for this article from CCC.

评价本文
*以上评分为匿名评价

版权归中华医学会所有。

未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

林奇综合征（Lynch syndrome）筛查涉及多个错配修复（mismatch repair，MMR）蛋白检测，以评估患者是否存在遗传性的DNA修复缺陷 ［ 1 ］ 。传统的MMR免疫组织化学（IHC）方法通常筛查4个蛋白（MLH1、MSH2、MSH6、PMS2，简称4-MMR）。4个标志物均为阳性表示该样本错配修复完整（mismatch repair perfect，pMMR），其中任意标志物阴性则称为错配修复缺陷（mismatch repair deficient，dMMR）。免疫检查点抑制剂的使用要求在结直肠癌、子宫内膜癌和胃癌中常规开展MMR IHC和微卫星不稳定性（microsatellite instability，MSI）检测 ［ 2 , 3 , 4 ］ ，随之而来会产生大量的切片和工作量。与MSI检测不同的是，MMR可提供原位的肿瘤蛋白表达信息，它可能会识别亚克隆表达丧失（肿瘤特定区域的表达丧失）的病例，这些缺失信息在进行MSI检测时可能会因DNA提取部位错误而遗漏 ［ 5 , 6 ］ 。若因样本量少，切片数量不足，则其他标志物与分子检查就成了难题。随着检测技术的进步和临床实践的积累，人们开始探讨是否可以通过检测较少的指标来达到相似的筛查效果。PMS2和MSH6是MMR基因中的重要成员，它们参与DNA错配修复过程，对于维持基因组稳定性至关重要。为了论证PMS2和MSH6双抗体（简称2-MMR）检测替代4-MMR检测在肿瘤dMMR筛查中的可行性，我们对近5年来南京大学医学院附属鼓楼医院病理科的实体肿瘤MMR数据进行回顾性汇总分析，对2-MMR和4-MMR筛查在识别dMMR中的灵敏度与特异度以及成本效益等综合对比，分析替代的可行性。如果2-MMR检测能够在保证筛查dMMR的同时降低检测成本和时间，那么它可能成为一个更具吸引力的选择。为此，我们就2-MMR检测对实现dMMR筛查的有效性进行论证。
MMR已被美国FDA批准为免疫检查点抑制剂的泛癌预测生物标志物 ［ 2 ］ 。MutSa和MutLa是错配修复机制中的关键蛋白。MLH1、MSH2的丢失会导致其异二聚体（PMS2、MSH6）失表达（原因在于PMS2、MSH6无法形成替代异二聚体），也就是说MLH1、MSH2不会出现单独阴性表达（MLH1或MSH2胚系突变）。然而PMS2、MSH6缺失，MLH1、MSH2却可以与另一种蛋白质（如PMS1、MLH3或MSH3）形成异二聚体而蛋白表达保留，也就是说PMS2和MSH6可以呈现单独阴性表达（PMS2或MSH6胚系突变）。因此通过MMR来筛查肿瘤dMMR时，单从MLH1和MSH2来看，并不能完全预测PMS2和MSH6的状态 ［ 3 , 4 ］ 。当增加PMS2和MSH6后，同时开展的4项MMR检测的IHC与MSI具有很高的一致性（91%~97%） ［ 4 ］ 。结直肠癌分子生物标志物检测专家共识中提到可以将MMR 4个项目精简为PMS2和MSH6双抗体检测 ［ 4 ］ 。Aiyer等 ［ 5 ］ 则较早提出只检测PMS2和MSH6可以反推出dMMR，并且可实现与检测4个指标相同的预测效果，得到很多研究者响应。正如Shia等 ［ 6 ］ 所建议，对dMMR的筛全率构成了双抗体进行MMR IHC筛查的证据。
试读结束，您可以通过登录机构账户或个人账户后获取全文阅读权限。
参考文献
[1]
Vilkin A , Halpern M , Morgenstern S ,et al. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation?[J]. Hum Pathol, 2014,45(10):2029-2036. DOI: 10.1016/j.humpath.2014.07.005 .
返回引文位置Google Scholar
百度学术
万方数据
[2]
中国抗癌协会大肠癌专业委员会遗传学组. 遗传性结直肠癌临床诊治和家系管理中国专家共识[J]. 中华肿瘤杂志, 2018,40(1):64-77. DOI: 10.3760/cma.j.issn.0253-3766.2018.01.013 .
返回引文位置Google Scholar
百度学术
万方数据
[3]
《结直肠癌分子生物标志物检测专家共识》编写组. 结直肠癌分子生物标志物检测专家共识[J]. 中华病理学杂志, 2018,47(4):237-240. DOI: 10.3760/cma.j.issn.0529-5807.2018.04.002 .
返回引文位置Google Scholar
百度学术
万方数据
[4]
中国抗癌协会妇科肿瘤专业委员会,中华医学会病理学分会,国家病理质控中心. 子宫内膜癌分子检测中国专家共识(2021年版)[J]. 中国癌症杂志, 2021,31(11):1126-1144. DOI: 10.19401/j.cnki.1007-3639.2021.11.012 .
返回引文位置Google Scholar
百度学术
万方数据
[5]
Aiyer K , Doeleman T , Ryan NA ,et al. Validity of a two-antibody testing algorithm for mismatch repair deficiency testing in cancer: a systematic literature review and meta-analysis[J]. Mod Pathol, 2022,35(12):1775-1783. DOI: 10.1038/s41379-022-01149-w .
返回引文位置Google Scholar
百度学术
万方数据
[6]
Shia J , Tang LH , Vakiani E ,et al. Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel[J]. Am J Surg Pathol, 2009,33(11):1639-1645. DOI: 10.1097/PAS.0b013e3181b15aa2 .
返回引文位置Google Scholar
百度学术
万方数据
[7]
吴鸿雁,王婷,付尧,等. 基于ISO15189认可体系持续改进免疫组织化学实验室的现代化建设[J]. 中华病理学杂志, 2018,47(12):982-984. DOI: 10.3760/cma.j.issn.0529-5807.2018.12.023 .
返回引文位置Google Scholar
百度学术
万方数据
[8]
Zhao G , Xiang G , Hu X ,et al. Universa l screening for Lynch syndrome in operated colorectal cancer by immunohistochemistry: a cohort of patients in Liaoning province, China [J]. Eur J Cancer Prev, 2023,32(4):337-347. DOI: 10.1097/CEJ.0000000000000775 .
返回引文位置Google Scholar
百度学术
万方数据
[9]
胡晓儒,徐灿,亢野,等. 658例结直肠癌错配修复蛋白的表达及其与临床病理特征的关系[J]. 中华病理学杂志, 2018,47(11):827-833. DOI: 10.3760/cma.j.issn.0529-5807.2018.11.003 .
返回引文位置Google Scholar
百度学术
万方数据
[10]
Hall G , Clarkson A , Shi A ,et al. Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma[J]. Pathology, 2010,42(5):409-413. DOI: 10.3109/00313025.2010.493871 .
返回引文位置Google Scholar
百度学术
万方数据
[11]
Mojtahed A , Schrijver I , Ford JM ,et al. A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas[J]. Mod Pathol, 2011,24(7):1004-1014. DOI: 10.1038/modpathol.2011.55 .
返回引文位置Google Scholar
百度学术
万方数据
[12]
O′Regan T , Chau K , Tatton M ,et al. Immunochemistry screening for Lynch syndrome in colorectal adenocarcinoma using an initial two antibody panel can replace a four antibody panel[J]. N Z Med J, 2013,126(1382):70-77.
返回引文位置Google Scholar
百度学术
万方数据
[13]
Aiob A , Kim YR , Kim K ,et al. A simplified two-marker immunohistochemistry strategy for Lynch syndrome screening in endometrial cancer patients[J]. Obstet Gynecol Sci, 2023,66(6):537-544. DOI: 10.5468/ogs.23124 .
返回引文位置Google Scholar
百度学术
万方数据
[14]
Stelloo E , Jansen A , Osse EM ,et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer[J]. Ann Oncol, 2017,28(1):96-102. DOI: 10.1093/annonc/mdw542 .
返回引文位置Google Scholar
百度学术
万方数据
[15]
Chao X , Li L , Wu M ,et al. Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer: a prospective cohort study in China[J]. Cancer Commun (Lond), 2019,39(1):42. DOI: 10.1186/s40880-019-0388-2 .
返回引文位置Google Scholar
百度学术
万方数据
[16]
Pearlman R , Markow M , Knight D ,et al. Two-stain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency[J]. Mod Pathol, 2018,31(12):1891-1900. DOI: 10.1038/s41379-018-0058-y .
返回引文位置Google Scholar
百度学术
万方数据
[17]
Nielsen S . External quality assessment for immunohistochemistry: experiences from NordiQC[J]. Biotech Histochem, 2015,90(5):331-340. DOI: 10.3109/10520295.2015.1033462 .
返回引文位置Google Scholar
百度学术
万方数据
[18]
王云帆,薛卫成. 结直肠癌MMR免疫组织化学异常表达的解读[J]. 临床与实验病理学杂志, 2024,40(6):572-575. DOI: 10.13315/j.cnki.cjcep.2024.06.003 .
返回引文位置Google Scholar
百度学术
万方数据
[19]
Flecchia C , Zaanan A , Lahlou W ,et al. MSI colorectal cancer, all you need to know[J]. Clin Res Hepatol Gastroenterol, 2022,46(9):101983. DOI: 10.1016/j.clinre.2022.101983 .
返回引文位置Google Scholar
百度学术
万方数据
[20]
Bao F , Panarelli NC , Rennert H ,et al. Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma[J]. Am J Surg Pathol, 2010,34(12):1798-1804. DOI: 10.1097/PAS.0b013e3181f906cc .
返回引文位置Google Scholar
百度学术
万方数据
[21]
Moreno E , Rosa-Rosa JM , Caniego-Casas T ,et al. Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer[J]. Diagn Pathol, 2020,15(1):84. DOI: 10.1186/s13000-020-01001-2 .
返回引文位置Google Scholar
百度学术
万方数据
[22]
Pannafino G , Alani E . Coordinated and independent roles for MLH subunits in DNA repair[J]. Cells, 2021,10(4):948. DOI: 10.3390/cells10040948 .
返回引文位置Google Scholar
百度学术
万方数据
[23]
Tamura K , Kaneda M , Futagawa M ,et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome[J]. Int J Clin Oncol, 2019,24(9):999-1011. DOI: 10.1007/s10147-019-01494-y .
返回引文位置Google Scholar
百度学术
万方数据
[24]
Niu BT , Hammond R , Leen S ,et al. Two versus four immunostains for Lynch syndrome screening in endometrial carcinoma[J]. Histopathology, 2019,75(3):442-445. DOI: 10.1111/his.13898 .
返回引文位置Google Scholar
百度学术
万方数据
[25]
Cohen R , Hain E , Buhard O ,et al. Association of primary resistance to immune checkpoint Inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite Instability or mismatch repair deficiency status[J]. JAMA Oncol, 2019,5(4):551-555. DOI: 10.1001/jamaoncol.2018.4942 .
返回引文位置Google Scholar
百度学术
万方数据
[26]
Wang F , Wang ZX , Chen G ,et al. Expert opinions on immunotherapy for patients with colorectal cancer[J]. Cancer Commun (Lond), 2020,40(10):467-472. DOI: 10.1002/cac2.12095 .
返回引文位置Google Scholar
百度学术
万方数据
[27]
Pei F , Wu J , Zhao Y ,et al. Single-agent neoadjuvant immunotherapy with a PD-1 antibody in locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer[J]. Clin Colorectal Cancer, 2023,22(1):85-91. DOI: 10.1016/j.clcc.2022.11.004 .
返回引文位置Google Scholar
百度学术
万方数据
备注信息
A
吴鸿雁，Email： mocdef.yabylgjn8281nayiad
B

王朝姗：研究构思、病例收集、数据分析、论文撰写、文章修改；张标：数据分析、检测技术帮助；孙琦：数据分析、结果判读；杨军：检测技术帮助；崔晓宾：结果判读、检测技术帮助；吴鸿雁：研究设计、病例收集、结果判读、文章修改、指导性意见

C
王朝姗, 张标, 孙琦, 等. PMS2和MSH6双抗体检测在肿瘤错配修复缺陷筛查中的运用[J]. 中华病理学杂志, 2025, 54(2): 126-134. DOI: 10.3760/cma.j.cn112151-20240531-00354.
D
所有作者声明无利益冲突
评论 （0条）
注册
登录
时间排序
暂无评论，发表第一条评论抢沙发
最新推荐
更多
2016年中国恶性肿瘤流行情况分析
郑荣寿 等
中华肿瘤杂志 2023,45(03)
HLA抗体检测中重点问题的专家共识
中国输血协会HLA专委会 等
中华器官移植杂志 2022,43(03)
错配修复缺陷的子宫内膜样腺癌中微卫星不稳定性分析
张煜涵 等
中华病理学杂志 2021,50(05)
MLH1、MSH2、MSH6、PMS2在结直肠癌组织中的表达及临床意义
陈明枝 等
中国实用医刊 2021,48(15)
MedAI助手（体验版）
文档即答
智问智答
机器翻译
回答内容由人工智能生成，我社无法保证其准确性和完整性，该生成内容不代表我们的态度或观点，仅供参考。
生成快照
文献快照

你好，我可以帮助您更好的了解本文，请向我提问您关注的问题。

0/2000

《中华医学会杂志社用户协议》 | 《隐私政策》

《SparkDesk 用户协议》 | 《SparkDesk 隐私政策》

网信算备340104764864601230055号 | 网信算备340104726288401230013号

技术支持：

历史对话
本文全部
还没有聊天记录
设置
模式
纯净模式沉浸模式
字号
小中大