Overall, we did not observe a statistically significant association between smoking and CRC. Duration and pack years of smoking were associated with an increased risk of MSI-H CRC; however, the tests for heterogeneity across categories of MSI status did not reach statistical significance. Our data also suggest that the associations between CRC and both smoking and alcohol consumption were stronger for rectal cancer than for colon cancer, although these differences were not statistically significant.
Results from two recent meta-analyses have suggested a small, but statistically significant association between CRC and smoking status, with evidence that the association is apparent following a long duration of smoking (1
). While we did not observe any statistically significant associations for CRC overall, our data are compatible with the summary ORs estimated in these reports. The meta-analysis data also suggested a stronger association for rectal cancer than for colon cancer (1
), in general agreement with our findings.
Our data suggest that alcohol consumption is associated with a small increased risk of CRC only for males, and that the association may be stronger for rectal cancer than for colon cancer. A pooled analysis (4
) and a meta-analysis (3
) of prospective cohort studies have confirmed an increased risk of CRC for individuals who consume large amounts of alcohol. However, data evaluating different effects of alcohol by anatomic location in the colorectum have been mixed, and the data from prospective cohorts suggest that the association with alcohol is similar for colon and rectal cancers (3
). Previous studies have reported a stronger association between alcohol consumption and CRC in men than in women, and the WCRF/AICR report concluded that there was convincing evidence for a role of alcohol in CRC in males and probable evidence for a role in females (5
Several studies have previously reported a stronger association between smoking and MSI-H CRC than for MSS/MSI-L CRC. This association has biological plausibility, as sporadic MSI-H tumors have been hypothesized to arise from a serrated pathway rather than through the traditional adenoma-carcinoma sequence (18
), and the association between smoking appears to be stronger for serrated lesions than for adenomatous polyps (19
). The stronger association for MSI-H CRC was first reported by Slattery et al.
) in a large population-based case-control study of colon cancer (N=266 MSI-H cases). Three additional studies using either case-control (11
) or case-case (12
) comparisons have also supported a stronger association between smoking and MSI-H CRC. In contrast, results from two other studies have not supported this hypothesis (21
). A more recent publication suggested that the association between smoking and CRC may be restricted to tumors with the CpG island methylator phenotype (CIMP), regardless of MSI status (23
). CIMP status was not available for the tumors included in this analysis, so we were unable to evaluate this hypothesis.
The association between alcohol consumption and MSI status has been evaluated previously using case-control and case-case comparisons (12
). Three of these studies suggested that alcohol intake was more strongly associated with MSI-H CRC (12
), although the associations were modest and did not reach statistical significance in all studies. These studies did not evaluate the cases with MSI-L tumors as a separate subgroup, and our data suggest that the association between alcohol consumption and CRC risk is strongest in this subgroup. Further studies will be required to clarify this interesting relationship.
This study has several strengths, including the large number of tumors with microsatellite instability typing and the inclusion of MSI-L tumors as a separate subgroup. However, several limitations must be considered. This study uses a case-unaffected sibling design, and it is possible that this may have reduced our power to detect associations between CRC and the lifestyle factors investigated here if these factors were strongly correlated within families. Smoking and alcohol consumption were correlated within sibships in our study population (r = 0.21, p<0.0001 for pack years of smoking and r = 0.11, p<0.0001 for number of drinks per week) attenuating the association of these factors with CRC. There is also the possibility that the unaffected siblings have underlying, but undetected, CRC, which would lead to misclassification of the outcome variable. Recall bias may lead to inaccurate risk estimates if smoking and alcohol consumption were reported more accurately by cases than unaffected siblings. In addition, microsatellite instability status was not available for tumors from 31% of cases in this study; however, the overall associations between smoking, alcohol consumption and CRC risk did not differ substantially for cases with and without tumor MSI data.
In conclusion, we observed no statistically significant associations between smoking and CRC overall; however, we did observe statistically significant associations between smoking and rectal cancer, smoking duration and MSI-H CRC, and pack years of smoking and MSI-L CRC. Alcohol consumption was associated with a modest increased risk of CRC in males, and was also significantly associated with MSI-L CRC in both males and females. These results highlight the potential importance of incorporating tumor characteristics in studies of risk factors for CRC.