TGFBR1*6A may contribute to hereditary colorectal cancer.

PURPOSE: TGFBR16A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR16A, and TGFBR16A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR16A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR16A 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 TGFBR16A. 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. TGFBR16A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR16A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR16A 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: TGFBR16A may be causally responsible for a proportion of HNPCC occurrences.