Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: Clinical significance

Abstract

Background and Objectives: The aim of the study was to understand the importance of mismatch repair genes MLH1 and MSH2 in chemotolerance and prognosis of breast carcinoma (BC). Methods: First, the alterations (deletion/methylation/expression) of MLH1 and MSH2 were analyzed in 45 neoadjuvant chemotherapy (NACT)-treated and 133 pretherapeutic BC samples. The chemotolerant BC cells were characterized by treating two BC cell lines MCF-7 and MDA MB 231 with two anthracycline antitumor antibiotics, doxorubicin and nogalamycin.Results: The deletion frequencies were 32% to 38% in MLH1/MSH2 genes and promoter methylation frequencies were 49% to 62% in MLH1 and 41% to 51% in MSH2 in both NACT-treated and pretherapeutic samples. The overall alteration of MLH1 and MSH2 was 58% to 71% in the samples. Reduced messenger RNA (mRNA) and protein expression were found in both the genes and it showed concordance with the molecular alterations. NACT-treated patients showed better prognosis. The chemotherapeutic drug induced increased mRNA/protein expression of the genes in BC cell lines was due to their promoter hypomethylation, as analyzed by quantitative methylation assay. This phenomenon was also evident in NACT-treated BC samples. Conclusion: MLH1/MSH2 genes play a critical role in the development of BC. Hypomethylation of MLH1/MSH2 genes might be important in chemotolerance of the disease. K E Y W O R D S breast carcinoma, doxorubicin/nogalamycin, MLH1/MSH2, neoadjuvant chemotherapy, promoter hypomethylation 1 | INTRODUCTION Breast carcinoma (BC) is the most common cancer among women worldwide. 1 It accounts for 25% of the cancer burden in Eastern Indian population. 2 Some of the etiological factors of BC are a genetic predisposition, exposure to ionization radiation, HPV infection, hormonal exposures, and obesity. 3-6 The early-onset BC (age of onset below 40 years) is more aggressive and shows lower survival rates compared J Surg Oncol. 2019;119:88-100. wileyonlinelibrary.com/journal/jso 88 | Abbreviations: 5-aza-dC, 5-aza-2′-deoxycytidine; BC, breast carcinoma; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HRP, horseradish peroxidase; MAI, microsatellite size alterations of one allele; MAII, microsatellite size alterations of two

Commentary: Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

“…The previously reported significant prognostic role of dMMR in TNBC (6,15) has not been confirmed by Ren et al because they found only 1 IHC dMMR and no MSI-H cases. In this respect, a study by our group focusing on MMR patterns of expression showed a better prognosis for TNBC tumors with MMR proteins perturbations (5).…”

“…The previously reported significant prognostic role of dMMR in TNBC ( 6 , 15 ) has not been confirmed by Ren et al. because they found only 1 IHC dMMR and no MSI-H cases.…”

“…The topic is of great importance considering the growing interest on the implementation of consistent MMR testing for prognostication, immune checkpoints inhibitors (ICI) prediction, and identification of therapy resistance/susceptibility in both adjuvant and neoadjuvant settings (6)(7)(8). To date, in the neoadjuvant setting, several clinical trials have examined the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade in early high-risk TNBC (9)(10)(11).…”

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

“…The assembly will initiate endonuclease activity of PMS2 which createssingle-strand breaks close to the mismatch and allows for the removal of thewrong-inserted base by exonuclease 1 (EXO1) seems to be more frequent [31]. Several studies confirmed that MMR deficiency is significantly associated with an increased risk of death in breast cancers, particularly in the HR+ group [21,29,32]. Despite this recognized prognostic role, the predictive value of MMR alterations is still controversial in these tumors [33].…”

Genetic and epigenetic modifications of HPDL and SOX17 associated with breast cancer prognosis: a study based on The Cancer Genome Atlas

“…Upstream regulators control BRCA tumor growth [20]. However, MLH1/MSH2, methylation product of the DNMT gene may be important for the chemotherapeutic tolerance of BRCA [21,22].…”