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

Although a positive association between cigarette smoking and colorectal ad enoma development is consistently found, the association with colorectal ca ncer remains controversial. We evaluated the potential roles of p27(Kip1) a nd 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 B uffalo General Hospital and 326 healthy controls responded to a standardize d questionnaire on colorectal cancer risk factors including detailed inform ation on their history of cigarette smoking; 110 of the patients' tumours w ere available for immunohistochemical analysis of p27(Kip1) and bcl-2 prote in overexpression. An avidin-biotin immunoperoxidase procedure was used to determine expression after incubation with mouse monoclonal p27(Kip1) and m ouse monoclonal bcl-2 antibodies, respectively. A statistically significant trend for total pack-years of smoking was found when p27(Kip1) positive ca ses were compared with p27(Kip1) negative cases (trend test, p = 0.007). Al though a weak inverse association was observed with smoking exposure among p27(Kip1) negative tumour cases in comparison to controls, a significant do se-response association was seen with p27(Kip1) positive tumours. The relat ive 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 t hose 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 co mpared 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 dif ferences in associations between cigarette smoking and expressions in p27(K ip1) and bcl-2. Our data suggest that bcl-2 overexpression (or a bcl-2 depe ndent pathway) is associated with cigarette smoking in the development of c olorectal cancer, whereas a loss of p27(Kip1) expression is not. These asso ciations indicate that there is aetiological heterogeneity in colorectal ca ncer development, and that they can indirectly allude to where these change s in protein expression occur in the adenoma-carcinoma sequence (i.e. early versus late events).