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The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

ABSTRACT: Both colorectal (CRC, 15%) and endometrial cancers (EC, 30%) exhibit microsatellite instability (MSI) due to MLH1 hypermethylation and silencing. The MLH1 promoter polymorphism, rs1800734 is associated with MSI CRC risk, increased methylation and reduced MLH1 expression. In EC samples, we investigated rs1800734 risk using MSI and MSS cases and controls. We found no evidence that rs1800734 or other MLH1 SNPs were associated with the risk of MSI EC. We found the rs1800734 risk allele had no effect on MLH1 methylation or expression in ECs. We propose that MLH1 hypermethylation occurs by different mechanisms in CRC and EC.

SUBMITTER: Russell H

PROVIDER: S-EPMC7346630 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

Russell Holly H Kedzierska Katarzyna K Buchanan Daniel D DD Thomas Rachael R Tham Emma E Mints Miriam M Keränen Anne A Giles Graham G GG Southey Melissa C MC Milne Roger L RL Tomlinson Ian I Church David D Spurdle Amanda B AB O'Mara Tracy A TA Lewis Annabelle A

Clinical epigenetics 20200708 1

Both colorectal (CRC, 15%) and endometrial cancers (EC, 30%) exhibit microsatellite instability (MSI) due to MLH1 hypermethylation and silencing. The MLH1 promoter polymorphism, rs1800734 is associated with MSI CRC risk, increased methylation and reduced MLH1 expression. In EC samples, we investigated rs1800734 risk using MSI and MSS cases and controls. We found no evidence that rs1800734 or other MLH1 SNPs were associated with the risk of MSI EC. We found the rs1800734 risk allele had no effect ...[more]

PMID: 32641106

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Project description:PurposeMicrosatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph).Experimental designOf > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses.ResultsCompared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively).ConclusionsMLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

Project description:BackgroundMicrosatellite instability (MSI) status is an important indicator for screening patients with endometrial cancer (EC) who have potential Lynch syndrome (LS) and may benefit from immunotherapy. This study aimed to develop a magnetic resonance imaging (MRI)-based radiomics nomogram for the prediction of MSI status in EC.MethodsA total of 296 patients with histopathologically diagnosed EC were enrolled, and their MSI status was determined using immunohistochemical (IHC) analysis. Patients were randomly divided into the training cohort (n=236) and the validation cohort (n=60) at a ratio of 8:2. To predict the MSI status in EC, the tumor radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images, which in turn were selected using one-way analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (LASSO) algorithm to build the radiomics signature (radiomics score; radscore) model. Five clinicopathologic characteristics were used to construct a clinicopathologic model. Finally, the nomogram model combining radscore and clinicopathologic characteristics was constructed. The performance of the three models was evaluated using receiver operating characteristic (ROC), calibration, and decision curve analyses (DCA).ResultsTotals of 21 radiomics features and five clinicopathologic characteristics were selected to develop the radscore and clinicopathological models. The radscore and clinicopathologic models achieved an area under the curve (AUC) of 0.752 and 0.600, respectively, in the training cohort; and of 0.723 and 0.615, respectively, in the validation cohort. The radiomics nomogram model showed improved discrimination efficiency compared with the radscore and clinicopathologic models, with an AUC of 0.773 and 0.740 in the training and validation cohorts, respectively. The calibration curve analysis and DCA showed favorable calibration and clinical utility of the nomogram model.ConclusionsThe nomogram incorporating MRI-based radiomics features and clinicopathologic characteristics could be a potential tool for the prediction of MSI status in EC.

Dataset Information

The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

Publications

The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

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