Inactivation of MSH2 was frequently observed in endometrial cancer (EC) with microsatellite instability (MSI) or mismatch repair complex deficiency (dMMR). With respect to MSH2 deficiency (dMSH2), most of dMSH2 were caused by germline mutations in the MSH2 gene or EpCAM deletions. Meanwhile, heritable germline epimutations in MSH2 reported in a few Lynch syndrome families that lacked germline mutations in the MSH2 gene. We previously provided evidence for frequent MSH2 hypermethylation in Lynch syndrome colorectal tumors with dMSH2 and MSH2 methylation may serve as the “second hit” at the wild-type allele. Herein, we examined precise epigenetic alteration in MSH2 promoter and tried to reveal associations to family history of Lynch syndrome related tumors.
We analyzed MSH2 promoter methylation status, as well as MLH1 methylation status, and expression status of the mismatch repair proteins (MLH1, MSH2, PMS2, and MSH6) by immunohistochemistry in 326 EC patients. DNA was extracted from formalin-fixed, paraffin-embedded tissue, and analyzed MSI status by four mononucleotide markers and both MLH1 and MSH2 promoter methylation status by a fluorescent quantitative bisulfite PCR assay.
MSI or dMMR was observed in 82 (25.2%) or 89 ECs (27.3%), respectively. ECs with dMSH2 were observed in 18 (5.5%) of 326 ECs (20.2% of dMMR). MSH2 promoter methylation was detected in 8 tumors (2.5% in 319 tumors excluding not available 7 ECs), and significantly correlated with dMSH2 (P = 0.0072, Fisher's exact probability test). Then, we also examined the family history of first-degree relatives. In this cohort, although patients with dMMR were significantly associated with family history of Lynch syndrome related tumor (P = 0.0312), patients with this family history are more frequently observed in patients with dMSH2 (P = 0.0052). Interestingly, patients with MSH2 promoter methylation were strongly associated with the family history of Lynch syndrome related tumor (P = 0.0053), though patients with MLH1 methylation were not (P = 0.8345).
MSH2 methylation significantly correlated with ECs with dMSH2 and may have strong relation with family history of Lynch syndrome related tumor, suggesting it takes a role as “second hit” to the MSH2 gene.
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All authors have declared no conflicts of interest.