Cancer spectrum among Irish DNA mismatch repair gene mutation carriers.

Abstract

424 Background: Pathogenic germline mismatch repair (MMR) mutations confer a high lifetime risk of colorectal cancer (CRC). Certain extra-colonic malignancies are also considered part of the Lynch syndrome (LS) spectrum including endometrial cancer, gastric, ovarian, small intestine, uroepithelial, pancreas, brain and skin cancer. A genotype-phenotype association has been reported. MSH2 mutation carriers appear to have a higher risk of developing extra-colonic cancer than individuals with a MLH1 mutation. We investigated the cancer spectrum in Irish LS kindreds and the likely association of these cancers with MMR deficiency. Methods: We identified 52 LS patients and family members with confirmed pathogenic DNA MMR mutations among 14 kindreds. Clinical data was extracted from the medical records and cancer diagnoses were confirmed from medical records and pathology reports. Tumour tissue was acquired. Immunohistochemistry (IHC) was completed for 4 MMR proteins and tumour lymphocyte infiltration is ongoing. Results: Spectrum of cancers identified include: CRC, endometrial , gastric, ovarian, renal, breast, prostate, urothelial, NHL, CML, lung, vocal cord, sebaceous carcinoma and cervix. Median age of diagnosis was 44. Thirteen individuals were diagnosed with two primary malignancies, 11 individuals were diagnosed with three primaries and one individual had four cancers. IHC analysis of three breast cancer cases demonstrated loss of MMR protein expression consistent with familial mutation. Conclusions: Early-onset cancers not traditionally considered manifestations of LS were identified in 14 LS kindreds. An additional 60 pedigrees are being worked up and further IHC and lymphocyte quantification will be reported at the meeting. An expanded LS-associated spectrum of malignancies may exist in certain families.