The influence of cigarette smoking on CRC risk for individuals with Lynch syndrome is not well understood. There is limited evidence suggestive of an increased risk for smokers but the studies have been small (18
). Given the large sample size and extensive information on smoking habits in the present study, we were able more fully to examine the association between smoking and CRC. We found that among MMR gene mutation carriers, compared with never smokers there was a statistically significant increased risk of CRC for current smokers and a lower risk for former smokers. An inverse association with smoking was evident for those who smoked fewer than 10 cigarettes per day and, for former smokers, the younger they were when they quit the less likely they were to develop CRC.
In the general population, the relationship between smoking and CRC remains somewhat inconsistent (13
). Smoking has, however, been found to be associated with a subset of CRC—namely, tumors exhibiting MSI. Slattery et al., in two separate case-control studies, examined the association between smoking and CRC risk for people with a family history and MSI-positive disease (16
). They found an earlier age at onset of CRC for subjects with a known family history of cancer and an increased risk of MSI-positive CRC for smokers (OR = 1.6; 95% CI, 1.0 – 2.5 for men; and OR = 2.2; 95% CI, 1.4 – 3.5 for women). The association of smoking with MSI-positive tumors was strongest for current smokers (OR = 2.3; 95% CI, 1.5 – 3.3). However, because a family history and MSI-positive tumors are not necessarily indicative of Lynch syndrome, caution is required in generalizing these results to people specifically with Lynch syndrome. (Even though MSI is a characteristic of Lynch syndrome CRC tumors, about 10-15% of non-Lynch CRC tumors are MSI positive because of hypermethylation of the promoter region of MLH1
). Using the same case-control data, Samowitz et al. (29
) found an association of smoking with CpG island methylator (CIMP) phenotype and BRAF mutations suggesting that the mechanism for the observed association may be induction of CpG island methylation. Again, very few Lynch-syndrome-associated tumors have a CIMP-high status or BRAF mutations (30
), so this epigenetic mechanism cannot explain an association between smoking and CRC in Lynch syndrome.
Two previous studies examined the association between smoking and CRC for people with Lynch syndrome. Watson et al. (19
), studied 330 mutation carriers and found a 43% increased risk of CRC for smokers (HR = 1.43; P = 0.04). However, because 25% of the participants were deceased, the smoking history obtained by family report or medical records was limited; thus the study compared non-smokers with smokers but did not report on other smoking variables. Another recent study by Diergaarde et al. (18
) involving 145 cases and 103 controls (not all of whom were confirmed MMR mutation carriers) found a 2.4-fold increased risk of CRC for current smokers (OR = 2.4; 95% CI, 1.1 – 5.3), consistent with our results but no association for former smokers.
Although increased risk of CRC for current smokers and declining risk after quitting are consistent with the known carcinogenicity of cigarette smoke, an inverse association with smoking among former smokers is difficult to explain. One can hypothesize that the former smokers in our study were a more heterogeneous group that included everyone from light smokers who had a history of smoking just 1 cigarette/day for 3 months to regular heavy former smokers. Because we also found that light smokers (1-10 cigarettes per day) and those that smoked for less than 10 years were at decreased risk, it is possible that occasional light smoking has an inverse association. However, the possibility that potential biases may give rise to this pattern cannot be ruled out. It is pertinent to point out that this is a study of people who have participated and given a blood sample. The unaffected mutation carriers are generally people in CRC families who have been motivated to participate; it is possible that they are more likely to be quitters than cases. Although the proportion of unaffected carriers who ever smoked was 49%, compared to 42% in the general population (32
), the proportion of quitters was higher for the unaffected (31%) than the cases (27%). Hence, the inverse association in former smokers could be due to participation bias by health-aware unaffected people.
A further possibility is that smoking acts only on a subset of MMR-mutation carriers, causing an earlier onset of CRC. This may eliminate susceptibles from the smoking group, ensuring that, among those with long smoking histories, there will be a higher proportion of carriers who are resistant to tobacco: this group will be overrepresented among quitters, resulting in an inverse association with smoking.
Finally, drawing upon studies of smoking and breast cancer risk in BRCA1/2 mutation carriers: separate studies have reported a reduced risk for smokers (33
), no association (35
), and increased risk (37
). In the largest and most recent of these studies (37
), it was suggested that inclusion of prevalent cases interviewed or tested many years after diagnosis may have resulted in the inverse association with smoking seen in earlier studies. To avoid this bias, the authors suggest that the interval between cancer diagnosis and testing or interview/questionnaire completion should be minimal. Our data were collected over more than 10 years and therefore include prevalent cases of CRC: the median difference between diagnosis and questionnaire completion being 6 years. However, to overcome this source of bias, we limited the smoking exposure to that before age at diagnosis or censoring.
Lastly, the results of our stratified analysis showed that the HR for current smokers for the birth cohort of 1960 or later was higher than for the earlier three cohorts. However, this cannot be explained by change in smoking behavior over the years since in our data these were not heavier or longer term smokers than the other cohorts. It is possible that attributes of cigarettes may have changed over the years and although our results are based on a small subsample, it does raise the possibility that the more recent cigarettes may be more harmful.
Potential limitations of this study include an inability to account for the potential confounding effect of other known environmental and lifestyle exposures, such as physical activity; alcohol, aspirin and calcium use; fruit and vegetable intake; and body mass index because we lacked complete data for these variables. Strengths include a large sample size and detailed smoking history. Furthermore, risk estimates were corrected for possible selection bias by application of appropriate weights (23
) and for familial correlation (26
We evaluated the association between smoking and the risk of CRC using a cohort of verified MMR-mutation carriers. We found an increased risk of CRC for current smokers and a decreased risk for former, short-term and light smokers that requires further confirmation, preferably in prospective studies, along with an investigation of the underlying biology of the relationship. The positive association between current smoking and increased colorectal cancer risk provides additional evidence to recommend avoidance of smoking for people genetically predisposed to CRC to reduce their risk.