Epigenetic silencing of MLH1 as a prognostic factor for endometrial cancer recurrence

Introduction/Background Aberrant DNA methylation is a common phenomenon in different types of cancer, but its patterns, causes, and consequences are poorly defined. Promoter hypermethylation of the DNA mismatch repair (MLH1) has been implicated in prognosis of endometrial cancer (EC). Methodology Fifty women diagnosed with endometrioid-type endometrial adenocarcinoma from 2018–2021 at the Institute of Oncology of Moldova were included in this study. DNA was isolated from plasma, formalin-fixed, paraffin-embedded tumor. The methylation status of the MLH1 gene was determined using the Methylation specific Polymerase Chain Reaction (MS-PCR) method and specific primers for both unmethylated and methylated fragments. (figure 1). Results Clinical and pathological characteristics for the 50 endometrial cancer patients are summarized in table 1. The mean age of the cohort was 59,9 ± 0,64 years (range, 39–87), and most of the patients had early stage (Stage I or II), grade 2 tumors with less than 50% myometrial invasion. The mean tumor size was 4,2 cm and the mean depth of invasion 0,5cm. Myometrial lymphatic/vascular space and perineural invasion was present in nearly half the tumors and was much more common in stage II cases. Overall, 80% of the patients with EC had intact tumors, while 20% had hypermethylation of MLH1 (table 2). The presence of MLH1 epimutation was observed in 22.0% of EC patients in stage I and only in 2 patients in stage II. Conclusion Recent developments in the field of epigenetics, especially studies of DNA methylation, have provided valuable insights for understanding the role of epigenetic alterations in normal cellular processes and abnormal changes leading to endometrial carcinogenesis. Promoter hypermethylation of MLH1 displayed a direct correlation with increasing age, poor differentiation of tumor, presence of myometral and limphovascular invasion. These phenotypes may underlie the different developmental pathways that are known to occur in endometrial cancer.peer-reviewe

Analysis of the molecular profile of endometrial cancer depending on microsatelite instability

Introduction/Background MLH1 is the MMR gene most frequently mutated or epimutated in endometrial cancer and its hypermethylation is found in the vast majority of MMR-deficient EC cases. The high rate of raw data accumulation with reference to cancer genomics as well as the development of bioinformatics algorithms necessary for the re-analysis of cohorts are key elements for obtaining new smart data. Methodology In the present study we aimed to re-analyze a set of genomic data obtained by sequencing 197 EC samples and downloaded from the public database cBioPortal for Cancer Genomics - Endometrial Cancer (MSK, 2018). The aim of the research was to separate the genomic data into two cohorts based on the presence or absence of microsatellite instability and analyze the molecular profile of these cohorts. Results As a result, two sets of data were obtained: SM (Microsatellite Stability) – 153 samples IM (Microsatellite Instability) – 25 samples In the MS cohort, an almost 2-fold higher frequency of changes in the tumor suppressor TP53 is observed, while in IM – a considerably increased rate of PTEN, ARID1A, MLL2, JAK1, POLE, MLH1, MSH6, MSH2 and PMS1 mutations (figure 1). SNV (Single Nucleotide Variation) classes in the IM group compared to SM have higher rates of T>C transitions that are associated with mutational signature no. 5 and lower C>G transversions - markers of signature 13 (figure 2). TMB in the two study groups revealed an index of less than 10 mut/Mb in MS and more than 10 mut/Mb in MI (figure 3). Conclusion Comparative analysis of molecular data in the two subtypes of CE reveals major differences in the mutational profile. A higher frequency of deletions with the displacement of the reading frame is observed in the SI cohort. TMB index in IM reveals tumors with MI have a better response to treatment with immune checkpoint inhibitors.peer-reviewe