Abstract 4277: Clinicopathological significance of endometrial cancer with MSH2 deficiency
Authors: Haraga Junko , Nagasaka Takeshi , Nakamura Keiichirou , Haruma Tomoko , Nishida Takeshi , Nyuya Akihiro , Yasui Kazuya , Masuyama Hisashi , Fujiwara Toshiyoshi , Hiramatsu Yuji 
Published: July 2017

Abstract
Background: Endometrial cancer accounts for the second percentage of Lynch syndrome related tumors following colorectal cancer. Inactivation of MSH2 was frequently observed in endometrial cancer with microsatellite instability (MSI) or mismatch repair complex deficiency (dMMR). With respect to MSH2 deficiency (dMSH2), not like MLH1 deficiency, most of dMSH2 were caused by germline mutations in the MSH2 gene or germline EpCAM deletions. Meanwhile, heritable germline epimutations in MSH2 have been 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.
Materials and Methods: In this study, 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 a cohort of 138 endometrial cancer tissues surgically resected at Okayama University Hospital. DNA was extracted from formalin-fixed, paraffin-embedded tissue, analyzed MSI status by four mononucleotide markers and both MLH1 and MSH2 promoter methylation status by a fluorescent quantitative bisulfite PCR assay.
Results: Endometrial cancers displaying MSI or dMMR were observed in 40 (29.0%) or 41 cases (29.7%), respectively. Endometrial cancers with MSH2 deficiency were observed in eight (5.8%) of 138 tumors (19.5% of dMMR). MSH2 promoter methylation was present in 7 cases (5.1% in 138 tumors), and significantly correlated with dMSH2 (P=0.0041, Fisher's exact probability test). Then, we also examined the family history of first-degree relatives retrospectively. In this cohort, although patients with MMR deficiency were significantly associated with family history of Lynch syndrome related tumor (P&lt;0.001), patients with this family history of Lynch syndrome related tumor are more frequently observed in patients with dMSH2 (P=0.0347). Interestingly, patients with MSH2 promoter methylation were strongly associated with this family history of Lynch syndrome related tumor (P=0.002), though patients with MLH1 methylation were not (P=0.0878).
Conclusions: In this study, we demonstrated that MSH2 methylation significantly correlated with dMSH2 and may have strong relation with family history of Lynch syndrome related tumor, taking a role as “second hit” to the MSH2 gene.
Citation Format: Junko Haraga, Takeshi Nagasaka, Keiichirou Nakamura, Tomoko Haruma, Takeshi Nishida, Akihiro Nyuya, Kazuya Yasui, Hisashi Masuyama, Toshiyoshi Fujiwara, Yuji Hiramatsu. Clinicopathological significance of endometrial cancer with MSH2 deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4277. doi:10.1158/1538-7445.AM2017-4277