Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals

Germline variants in theAPCandMUTYHgenes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence ofAPC, monoallelicMUTYHand biallelicMUTYHgermline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225 individuals with colorectal adenomas who had germlineAPCandMUTYHtesting at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency ofAPCandMUTYHvariants between AJ and OA, and examinedAPCp.I1307K and monoallelicMUTYHcarrier phenotypes using logistic regression. PathogenicAPCvariants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%;P = 0.09); biallelicMUTYHvariants in 2/285 (1%) AJ and 399/6940 (6%) OA (P < 0.0001);APCp.I1307K in 35/285 (12%) AJ and 29/6940 (1%) OA (P < 0.0001); and monoallelicMUTYHin 2/285 (1%) AJ and 133/6940 (2%) OA (P = 0.06). MonoallelicMUTYHvariants were significantly associated with having a personal history of CRC, regardless of ancestry (OR 1.78; 95% CI 1.21-2.49;P < 0.01), but no significant association was found betweenAPCp.I1307K variants and personal history of CRC (OR 1.38; 95% CI 0.79-2.44;P = 0.26). Ashkenazim with colorectal adenomas rarely have monoallelic or biallelicMUTYHvariants, suggesting different genetic etiologies for polyposis in AJ compared to OA individuals. AJ ancestry assessment may be important in clinical evaluation for polyposis.