首页 > 期刊杂志 > 正文

Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma.

Pasanen A,Loukovaara M,Bützow R
阅读:232 Modern PathologyVolume 33 Issue 7, July 2020:1443-1452 

Abstract

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.

摘要

full text

我要评论

0条评论