Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma

Huijuan Ge,Xu Cai,Wenhua Jiang,Guangqi Qin,Yanzi Gu,Xiaoyu Tu,Yaoxin Xiao,Wentao Yang,Rui Bi

doi:10.1186/s13000-021-01071-w

Abstract

BackgroundOvarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). ARID1A mutation is an important pathogenetic mechanism in OCCC that leads to loss of ARID1A expression in approximately half of OCCCs. However, the correlation of MMR status and ARID1A deficiency is unclear. The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency.MethodsA cohort of 176 primary OCCC patients was enrolled and review included histological characteristics (nuclear atypia, necrosis, mitosis, stromal hyalinization, and background precursors) and host inflammatory response (tumor-infiltrating lymphocytes, peritumoral lymphocytes, intratumoral stromal inflammation and plasma cell infiltration). Immunohistochemical staining of MLH1, PMS2, MSH2, MSH6 and ARID1A was performed using tissue microarrays.Results dMMR was detected in 10/176 tumors (6 %), followed by MSH2/MSH6 (6/176), MLH1/PMS2 (3/176), and MSH6 (1/176). The average age of patients with dMMR was younger than that of patients with intact MMR (46 y vs. 53 y). Tumors with diffuse intratumoral stromal inflammation remained significantly associated after multivariate analysis. ARID1A expression was absent in 8 patients with dMMR (8/10), which is a significantly higher frequency than that observed in patients with intact MMR (80 % vs. 43.2 %).ConclusionsOur study indicates that diffuse intratumoral stromal inflammation of OCCCs is associated with dMMR, with loss of MSH2/MSH6 expression being most frequent. dMMR is strongly associated with the loss of ARID1A expression in OCCC.

Highlights

Lynch syndrome (LS) is an autosomal dominant predisposition toward neoplasia caused predominantly by germline mutations in one of four DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6 and PMS2 [1], and rarely by EpCAM deletions, which cause MSH2 promoter methylation and inactivation [2]
Several reports have demonstrated that tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocytes in endometrioid carcinoma indicate deficient MMR [12,13,14]
In the deficient MMR (dMMR) group, 2 patients had synchronous malignant tumors, and 2 patients had a history of hereditary nonpolyposis colorectal cancer (HNPCC)

Summary

Introduction

Lynch syndrome (LS) is an autosomal dominant predisposition toward neoplasia caused predominantly by germline mutations in one of four DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6 and PMS2 [1], and rarely by EpCAM (epithelial cell adhesion molecule) deletions, which cause MSH2 promoter methylation and inactivation [2]. A loss-offunction mutation in the normal allele increases cancer risk [3] and is the most common cause of colon cancer and familial endometrial carcinoma. It has been associated with an increased risk of other cancers, such as renal pelvis/ ureter, stomach, small bowel, and brain cancer [4]. Ovarian clear cell carcinoma (OCCC) is the second reported subtype of ovarian epithelial carcinoma that is closely related to LS, with a mean age at diagnosis of 55 years, and is strongly associated with endometriosis and adenofibromatous components [11]. Ovarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency

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