EDITORIAL

Cigarette Smoking and Microsatellite Instability: Causal Pathway or Marker-Defined Subset of Colon Tumors?

Alfred I. Neugut, Mary Beth Terry

Affiliations of authors: A. I. Neugut (Department of Medicine and Division of Epidemiology), M. B. Terry (Division of Epidemiology), Mailman School of Public Health and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY.

Correspondence to: Alfred I. Neugut, M.D., Ph.D., Division of Oncology, New York Presbyterian Hospital, 630 W. 168th St., PH18–127, New York, NY 10032 (e-mail: ain1{at}columbia.edu).

When the average person thinks of cigarette smoking and cancer, the cancers that come to mind are those of the lung and upper aerodigestive tract. Cancer researchers have also long recognized the etiologic association of cigarette smoking with a number of other cancers, such as those of the bladder and pancreas. Until quite recently, however, colon cancer, one of the most common cancers in the United States, was not recognized as being associated with cigarette smoking, this despite the fact that numerous studies (13) consistently found an association between cigarette smoking and adenomas, the precursor lesions for most cases of colon cancer.

This seeming paradox, that smoking may be related to colorectal adenomas but not to cancer, has generated much debate. One explanation may be that there is no paradox at all. For example, in two prospective cohort studies, Giovannucci et al. (4,5) reported twofold increases in risk of colon cancer after 35 years of smoking (4,5). Another long-term cohort study has supported these findings (6), although others have not (79). At this point, it is safe to say that the association observed between smoking and colorectal cancer has been inconsistent at best.

We and others (1013) have attempted to explain the paradox between the relatively strong and consistent association observed between cigarettes and newly diagnosed (1,3) and recurrent (14) adenomas versus the more elusive association with colon cancer; it would seem obvious that an outcome end point should have at least as strong an association with a risk factor as with an intermediate step (15). One possibility is that this phenomenon represents selection bias in the study of a relatively benign incidental finding on a screening/diagnostic test versus the diagnosis of a potentially fatal symptomatic disease. Another possibility is that there are two different classes of adenomas, those that are truly premalignant and those that are truly benign (nonprogressing), which may differ in their association with cigarette smoking (16,17). However, the prevalence of smoking has not been found to differ between patients with smaller versus larger adenomas (12,18), suggesting that smoking may be important to the formation of adenomas but not to their growth. Another possibility is that the odds ratios used in estimating associations with adenomas are not good approximations of the relative risk (11).

In this issue of the Journal, Slattery et al. (19) add an important bit of information in supporting the hypothesis that a link does indeed exist between cigarette smoking and at least certain colon cancers. Their study supports the view that cigarette smoking is more strongly associated with the group of cancers that have microsatellite instability (MSI). While MSI is found in the vast majority of colorectal cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, HNPCC constitutes only about 2%–5% of all colorectal cancers (2022). Among sporadic tumors, MSI has been found to occur as a somatic genetic mutation in about 11%–28%, or 15% on average (23), almost exactly the prevalence found in the study by Slattery et al. (19).

Molecular epidemiology has given scientists an additional tool to investigate underlying pathways by which risk factors may be operating. The impact of cigarette smoking on bladder cancers that overexpress p53 (24) and the impact of certain occupational exposures on acute myeloid leukemias with K-ras mutations (25) are two examples. The study by Slattery et al. (19) may prove to be just as influential by providing a potential mechanism to link cigarette smoking to colon cancer. Furthermore, their study provides some possible clues as to why this observation has been so inconsistent in the past. Because only a subset of colon cancers may be attributable to cigarette smoking, the observed relative risk in any given study between cigarette smoking and colon tumors would be highly dependent on the actual mix of MSI-positive versus MSI-negative tumors.

While this study sheds light on why cigarette smoking may have been inconsistently related to colon cancer, it raises additional questions about cigarette smoking, MSI, and adenomas. A few studies (23,26) have suggested that MSI is not common before adenoma formation. The cigarette smoking–MSI pathway may be functioning on the progression from adenoma to carcinoma rather than at earlier stages of the adenoma–carcinoma sequence; more research on this is needed, however. If smoking proves unrelated to MSI in adenomas, it may be worthwhile to revisit the usefulness of the adenoma-carcinoma model for certain risk factors.

The inverse association between MSI positivity and K-ras mutations observed in the study by Slattery et al. (19) gives additional evidence that there may be two molecularly distinct forms of colorectal cancer. Specifically, MSI-negative tumors have been associated both with p53 overexpression (27,28) and with K-ras mutations (19). These two groups of colon tumors have been referred to as loss of heterozygosity-positive—characterized by K-ras and p53 mutations—and MSI-positive colorectal cancers (28,29). If true, this would suggest that risk factors associated with MSI-positive tumors would be inversely associated with p53-positive tumors. Indeed, Freedman et al. (30) found that p53-negative colorectal cancers had an odds ratio of 1.84 (95% confidence interval = 1.00–3.37) with cigarette smoking, while they found no association between cigarette smoking and p53-positive colorectal cancer, consistent with the finding of Slattery et al. (19) that MSI-positive tumors, but not MSI-negative tumors, are associated with smoking. Whether these two subgroups of colorectal cancer represent clinically distinct categorizations as well (3134), as is true of estrogen receptor-positive and estrogen receptor-negative breast cancer, remains to be determined.

Analyses in the report by Slattery et al. (19) of other lifestyle risk factors do not consistently show different associations with MSI-positive versus MSI-negative colorectal cancers. However, they do suggest the possibility of an association between high body mass and MSI-negative cancers, consistent with the finding by Zhang et al. (35), that high body mass is associated with p53-positive cancers. Other studies (3638) have also found differential associations for p53 overexpression in colorectal cancer with other risk factors, although this literature is still scant. Future studies investigating risk factor patterns and colorectal cancer with a panel of markers would be helpful.

Finally, what are the next steps? Confirmation of these observations is critical. Exploration of the relationship of cigarette smoking, MSI, and different stages of the adenoma–carcinoma sequence are also obvious next steps. Elucidation of how tobacco smoke may cause MSI could lead to the development of methods for prevention. What explains the MSI–cigarette smoking association in colon tumors also demands investigation, particularly since access by the carcinogens in tobacco smoke to colonic mucosa seems highly indirect. As any good research study does, Slattery's study answers several questions but also raises additional ones. She and her colleagues provide one rationale why the smoking and colon cancer relationship has been so inconsistent; the question of why the smoking and adenoma relationship has been so consistent remains.

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