Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome)

Background: The marked variability in age at onset of colorectal cancer (CRC) in patients with hereditary non-polyposis colorectal cancer (HNPCC) makes management decisions difficult. Environmental factors governing the phenotypic variability of cancer-associated syndromes such as HNPCC have not been elucidated. Methods: We determined whether tobacco use would alter CRC risk in carriers of HNPCC-associated mutations, using a retrospective cohort study of germline mutation (hMLH1 or hMSH2) carriers from the Hereditary Cancer Institute at Creighton University, one of the oldest and largest registries of HNPCC patients. The main outcome measure was age at CRC onset, estimated by means of Cox proportional hazards modeling. Results: Tobacco use, hMLH1 mutation carriage (as opposed to hMSH2), and male sex were significantly associated with increased risk of CRC (hazard ratios, 1.43, 2.07, and 1.58, respectively). Alcohol use did not alter CRC risk. Conclusions: Smoking cessation should be an integral part of HNPCC management. This study underscores the gene × environment interactions in cancer development.