A184

Since a K-ras oncogene mutation is an early event in colorectal cancer development and cigarette smoking is thought to have an effect in early stages of colorectal tumorigenesis, smoking may be associated with the risk of colorectal cancer with K-ras oncogene mutations. This was investigated in the Netherlands Cohort Study on Diet and Cancer (NLCS) which was initiated in 1986 and included 120,852 men and women. Participants completed a self-administered questionnaire on risk factors for cancer at baseline. Using direct sequencing, K-ras mutation analysis of exon 1, codons 12 and 13, was completed successfully on DNA from archival paraffin-embedded tissue from 734 colorectal cancer cases who where identified during follow-up between 1999 and 2003. Accumulation of person time in the cohort was estimated through vital status follow-up of a subcohort of 5,000 men and women who were randomly selected after baseline exposure measurement. Using a case-cohort design, Cox proportional hazard analysis was used to estimate hazard ratios (RR) and 95% confidence intervals (CI) for colorectal cancer overall, and colorectal cancer with or without mutations in K-ras, and with or without G>A or G>T mutations in K-ras according to cigarette smoking status (never, ex- and current smoker), duration (years), frequency (cigarettes/day), pack years, age at first exposure, years since cessation, inhalation and filter usage. RR were adjusted for age, gender, family history of colorectal cancer, Body Mass Index, alcohol and coffee intake. Ex-smokers were at increased risk of colorectal cancer with wild type K-ras gene tumors when compared to never smokers (RR 1.26, 95% CI 0.96-1.66). This association was less clear for K-ras mutated tumors (RR 1.15, 95% CI 0.79-1.66) when comparing ex-smokers to never smokers. Current smokers were not at increased risk of colorectal cancer regardless of K-ras mutation status. The highest category of frequency (>20 cigarettes/day) and inhalation were associated with an increased risk of colorectal cancer with wild type K-ras gene tumors compared to never smokers, though not statistically significant (frequency: RR 1.24, 95% CI 0.90-1.71 and inhalation: RR 1.25, 95% CI 0.94-1.67). No clear associations were observed between any of the smoking variables and the risk of colorectal cancer with mutated K-ras gene tumors. Finally, none of the smoking variables where associated with the risk of colorectal cancer with specific G>A transitions or specific G>T transversions in K-ras. These results suggest that several smoking variables, i.e. past smoking, frequency and inhalation, may be associated with risk of colorectal cancer with wild type K-ras gene tumors. There were no apparent associations between smoking variables and the risk of mutated K-ras gene colorectal tumors.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]