The prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair deficient gastric cancer.

Abstract

380 Background: Approximately 2-4% of patients with primary colorectal cancer are estimated to be associated with Lynch syndrome. However, the prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair-deficient (dMMR) gastric cancer (GC) is not well understood. In this study, we investigated the frequency of dMMR GCs in unselected GCs and the prevalence of Lynch syndrome, as well as associated clinicopathologic features and molecular alterations in dMMR GCs. Methods: A total of 847 cases of unselected GCs from 2010 to 2012 were collected at Jeju National University Hospital. Immunohistochemistry for mismatch repair proteins (MMR), including MLH1, MSH2, MSH6, and PMS2, and MSI analysis were performed on representative tumor sections of surgically resected specimens. Follow-up genetic counseling and genetic and/or epigenetic alterations of the MMR genes were also investigated. Results: Loss of one or more MMR proteins and microsatellite instability-high were observed in 72 patients; 67 patients showed loss of MLH1/PMS2, 2 patients showed loss of PMS2 alone, and 3 patients with MSH2/MSH6. Genetic counseling demonstrated that ten patients had a family history of LS-associated cancers and nine patients had a history of metasynchronous cancers. Of the 72 patients, 65 revealed hypermethylation of the promoter region of MLH1. The subsequent genetic germline tests demonstrated 2 patients with MLH1 mutation, 3 with MSH2 mutation, and 2 with PMS2 mutation. Conclusions: dMMR tumors were identified in 72 (8.5%) of 847 unselected primary GCs. This study estimated that 0.8% of patients with unselected GC and 9.7% of patients with dMMR GC fulfilled the revised Bethesda criteria and are associated with Lynch syndrome. The detection of dMMR GCs and necessary genetic counseling/tests based on revised Bethesda criteria would help find Lynch syndrome in patients with GC. Clinical and immunophenotypical features of patients with dMMR GC. Age ≤ 50 years 5 (6.9) > 50 years 67 (93.1) Other malignancy history except GAC No 63 (87.5) Yes 9 (12.5) History of metachronous cancers Esophageal cancer 1 (1.4) Maxillary sinus cancer 1 (1.4) Papillary thyroid cancer 1 (1.4) Colorectal cancer 1 (1.4) Pancreatic cancer 1 (1.4) Breast cancer 1 (1.4) Breast cancer and malignant GIST 1 (1.4) Multiple HCCs 2 (2.8) History of Family with LS related cancers No 62 (86.1) Yes 10 (13.9) Fulfillment of the rBG No 63 (87.5) Yes 9 (12.5) MMR proteins Loss of MLH1 and PMS2 67 (93.1) Loss of PMS2 2 (2.8) Loss of MSH2 and MSH6 3 (4.2) Germline mutation test MLH1 mutations 2 (2.8) MSH2 mutations 3 (4.2) PMS2 mutations 2 (2.8)