Ashkenazim with APC*I1307K: Why Do Some Carriers Form Colon Neoplasms While Others Do Not?

Abstract

Purpose: The germline APC*I1307K mutation is a genetic risk factor for the development of colorectal neoplasms in Ashkenazi Jews. We compared risk factors, family history and specific genetic markers of carriers with and without known colorectal lesions in an attempt to understand why certain carriers of the APC*I1307K mutation develop lesions and other carriers do not. Methods: Available information included social history (cigarette, NSAID, and HRT use), family history, colonoscopic findings, and the histologic information about the lesions. Standard PCR based assays were performed on tissue or blood DNA for the germline mutations BLMash, MSH2*1906G>C, CRAC-1, MLH1*D132H and APC genotypes. Results: Nineteen (20.9%) of 91 APC*I1307K carriers did not have a colonic lesion despite one or more colonoscopies. Seventy-two (79.1%) of the 91 carriers had one or more adenomas and/or colorectal cancer based on history and pathology reports. The age of the APC*I1307K carriers with and without lesions at the time of first colonoscopy was 59.6 and 57.6 years, respectively. The average number of colonoscopies at the time of study-entry for patients with and without lesions was 3.1 and 2.2, respectively. Additionally, the average age when the first lesion was found in the group with lesions was 62.1 years. Both groups of patients carried only wild type for the BLMAsh, MSH2*1906G>C, CRAC-1, and MLH1*D132H gene variants, and there were no differences in the genotypes for the APC markers. There was a suggestion that a family history of colorectal neoplasm was more prevalent with those individuals with lesions than those without lesions. This difference did not reach statistical significance; however, the group without the lesions was quite small. Conclusion: It is not fully apparent why some carriers of the APC*I1307K mutation develop colorectal neoplasms and others do not. We have eliminated common risk factors and several other known germline risk mutations as contributory. There is a suggestion, nonetheless, that family history of colorectal lesions is a marker for such development. This, in turn could well be the result of additional unknown germline mutations, although common environmental factors or diet cannot be excluded.Table 1: Family history and risk factors for developing lesions in APC*I1307 K carriers with and without lesions