Expression of p27(Kip1) and bcl-2, cigarette smoking, and colorectal cancer risk

Although a positive association between cigarette smoking and colorectal adenoma development is consistently found, the association with colorectal cancer remains controversial. We evaluated the potential roles of p27(Kip1) and bcl-2 protein expressions in conjunction with cigarette smoking exposure and colorectal cancer risk in a hospital-based case-control study. A total of 163 colorectal cancer patients from Roswell Park Cancer Institute and Buffalo General Hospital and 326 healthy controls responded to a standardized questionnaire on colorectal cancer risk factors including detailed information on their history of cigarette smoking; 110 of the patients' tumours were available for immunohistochemical analysis of p27(Kip1) and bcl-2 protein overexpression. An avidin-biotin immunoperoxidase procedure was used to determine expression after incubation with mouse monoclonal p27(Kip1) and mouse monoclonal bcl-2 antibodies, respectively. A statistically significant trend for total pack-years of smoking was found when p27(Kip1) positive cases were compared with p27(Kip1) negative cases (trend test, p = 0.007). Although a weak inverse association was observed with smoking exposure among p27(Kip1) negative tumour cases in comparison to controls, a significant dose-response association was seen with p27(Kip1) positive tumours. The relative risk of developing a p27(Kip1) positive tumour was estimated to be 1.17 (95 % CI 0.54-2.54) for those with less than 20 pack-years, 1.95 (95 % CI 0.95-3.97) for those with 20-39 pack-years, and 2.25 (95 % CI 1.14-4.45) for those with greater than 39 pack-years of smoking exposure (trend test, p = 0.009) when compared with controls. When cases with bcl-2 expression were compared with cases without bcl-2 expression, suggestion of a trend was also observed with pack-years smoked (trend test, p = 0.09). In our study of 110 patients with sporadic colorectal cancer and 326 controls, we observed differences in associations between cigarette smoking and expressions in p27(Kip1) and bcl-2. Our data suggest that bcl-2 overexpression (or a bcl-2 dependent pathway) is associated with cigarette smoking in the development of colorectal cancer, whereas a loss of p27(Kip1) expression is not. These associations indicate that there is aetiological heterogeneity in colorectal cancer development, and that they can indirectly allude to where these changes in protein expression occur in the adenoma-carcinoma sequence (i.e. early versus late events).