TGFBR1*6A may contribute to hereditary colorectal cancer

Purpose TGFBR1*6A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR1*6A, and TGFBR1*6A homozygotes have a greater than 10.0% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR1*6A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR1*6A contributes to a proportion of mismatch repair (MMR) gene mutation-negative hereditary nonpolyposis colorectal cancer (HNPCC) patients. Patients and Methods A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR1*6A. Tumor microsatellite instability status was available for 95 patients. Results A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR1*6A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR1*6A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR1*6A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17). Conclusion TGFBR1*6A may be causally responsible for a proportion of HNPCC occurrences.