Results from our study support previous investigations demonstrating a positive association between cigarette smoking and colorectal polyps (12
). Furthermore, we confirmed results from studies done in other populations reporting that adenomas are associated with smoking separate from HPs (14
). Also, like these prior studies, we reported that cigarette smoking is more strongly associated with HPs than adenomas. For adenomas, previous studies reported ORs ranging from 1.3–1.6 associated with the highest level of smoking, and for HPs, the OR estimates ranged from 3.1 to 4.8 [5–7]. Based on these findings, we concur with Morimoto, et al
) that cases having both adenomas and HPs should be evaluated separately from those with only adenomas or only HPs. These analyses are in contrast to studies that include individuals with both adenomas and HPs in the adenoma case group (41
). In the instance of smoking, including those with both types of polyps in the adenoma case group, rather than putting them in their own separate group, would result in an inflation of the OR estimate for adenomas.
With the growing body of evidence that a subset of HPs may progress to cancer along a pathway that is distinct from the established adenoma-carcinoma sequence (43
), it is important to characterize risk factors for adenomas and HPs separately from one another, and to consider those with both types of polyps as an independent case group. However, cases with both types of polyps were different from the other case groups in that they necessarily had more than one polyp. When we restricted our analyses to adenoma only cases and HP only cases with multiple polyps, the OR estimate for smoking ≥ 22 pack-years increased by 8% for adenomas and by 32% for HPs (data not shown). This suggests that the stronger association noted in those with both polyp types may reflect the fact that these cases have multiple polyps, one of which is a hyperplastic polyp.
Our study results also suggest a positive association between charred meat consumption and distal/rectal HPs. We did not report statistically significant associations between charred red meat consumption or preparation and adenomas, in contrast to several such studies(1
). Risk estimates evaluating the association between servings of charred red meat per week and colorectal adenomas for these studies range between 1.11 and 2.73. Despite finding no statistically significant associations for charred red meat intake and adenomas, we reported a suggestion of elevated risks associated with consuming charred red meat, and these risk estimates were higher for adenomas in the distal colon/rectum.
Numerous studies have reported that the increased risk of colorectal polyps associated with smoking is exclusively in distal and rectal polyps; however, this has not been well-studied for meat intake, and further research is needed to determine if the association between charred meat consumption and colorectal polyps depends on polyp location. This information could provide clues to the mechanisms by which charred meat may promote polyp growth and contribute to increased colorectal cancer risk.
Our results do not support a strong association between mEH
polymorphisms and colorectal polyp risk. Other studies have evaluated the association between mEH
polymorphisms and colorectal polyps, and the results are inconsistent. Two studies reported significantly decreased risks of adenomas, ranging from a 30–44% reduction in risk, associated with the exon 3 His/His genotype (slower mEH activity) (27
). Five additional studies reported no association for the exon 3 polymorphism with adenomas (30
), and two of these also evaluated HPs and reported no association for HPs (31
). Each of the above studies evaluated the exon 4 polymorphism in relation to polyp risk, and only one reported a significant increased risk for adenomas (OR= 1.72) associated with the Arg/Arg genotype (faster mEH activity) (33
Of note is that the three studies reporting significant associations between colorectal polyps and mEH
polymorphisms all evaluated adenomas and not HPs, had large samples sizes (ranging from 772–991 cases and from 400–946 controls), and identified cases via sigmoidoscopy rather than colonoscopy (27
). Therefore, their case groups all have either rectal or distal colon polyps. It is possible that variations in mEH activity play a role in rectal and distal colonic neoplasia but not in other parts of the large bowel.
We attempted to explore this possibility in our data by evaluating genotype associations among cases with at least one left-sided or rectal polyp (data not shown). No significant associations were identified for the exon 3 polymorphism when we restricted our analyses to cases with left-sided or rectal polyps. However, for the Exon 4 polymorphism, the homozygous variant allele was associated with a statistically significant increase in the risk of being diagnosed with both types of polyps concurrently when at least one of these polyps was in the left colon or rectum [OR (95% CI): 2.48 (1.02–6.04)].
Consistent with our results, several studies examining an interaction between mEH
genotype or predicted mEH activity and cigarette smoking (29
) or consumption of charred meat (30
) did not find any gene-environment interactions. A subset of these studies examined charred meat intake as a potential modifier of the association between mEH
polymorphisms and colorectal neoplasia and reported results that were similar to smoking analyses, with the exception that one study reported evidence for a statistically significant interaction between predicted mEH activity and charred meat consumption (interaction p-value = 0.03) (32
). Among those with high charred meat consumption, Cortessis et al. (32
) found “rapid” mEH activity increased the risk of adenomas.
The present study has several strengths, including a well-characterized population of comparable cases and controls and standardized assessment of epidemiologic risk factors. In addition, since all cases and controls were evaluated via colonoscopy, we ensured that controls were, in fact, polyp-free. Finally, we evaluated functional polymorphisms with known effects on mEH activity, allowing us to examine a potential mechanism for smoking and charred meat induced neoplasia in the colon and rectum.
Despite these strengths, our findings should be interpreted in light of several limitations. We interviewed cases and controls after diagnosis, which may result in differential recall bias (44
). However, because polyps tend to be presented to patients as benign, case status is unlikely to greatly influence responses. Also, genotype was not known to study participants. Because we selected study participants who received a colonoscopy, our study population was likely healthier (45
), with less heavy smokers, and likely consumed less red meat than the greater Group Health population. This would potentially reduce our power to detect significant associations due to a lower prevalence of these exposures in our study population.
With the addition of the present study, eight studies have examined the role of mEH polymorphisms and colorectal polyp risk. However, there is still little consensus on the role that variations in mEH activity play in colorectal carcinogenesis, either directly or as a co-factor with environmental exposures to BaP. The only studies that report significant associations between mEH polymorphisms and colorectal polyps focused on the distal colon and rectum and had large samples sizes. In addition, in our own analyses, the associations between polyps and smoking and charred meat consumption were stronger in the distal colon/rectum.
Therefore, we recommend that future studies of mechanisms for BaP induced colorectal carcinogenesis recruit enough participants with left-sided and rectal tumors that stratified analyses by site can be conducted with adequate power. Also, because clinic-based colonoscopy or sigmoidoscopy studies may have lower levels of heavy smoking and charred meat consumption, future studies need to allow for larger sample sizes to adequately address questions on gene-environment interactions.
Finally, given the lack of strong evidence for the role of mEH
in colorectal carcinogenesis, other potential mechanisms for BaP associated colorectal neoplasia need to be fully evaluated. One such mechanism involves one-electron oxidation of BaP, producing radical cations and resulting in depurinating DNA adducts (46
). These adducts are unstable, and they break off from the DNA (48
), leaving apurinic sites repaired by error-prone base-excision repair (49
). For this reason, BaP’s association with unstable DNA adducts may be a much more important mechanism for carcinogenesis than the formation of stable adducts, like BPDE. Further research is required to determine mechanisms for BaP-related carcinogenesis and potential genetic effect modifiers of this pathway.