Consistent with previous observational studies (13
), our findings indicate that BMI and adult weight gain are associated with an increased risk of colorectal cancer; a novel aspect of our study is the inclusion of tumor MSI data and the finding that overweight and obesity were associated with increased risks of MS-stable and MSI-low tumors, but not with the risk of MSI-high tumors. These data add further evidence that excess body weight is a potentially avoidable cause of colorectal cancer. The risk estimate for recent BMI was higher for men than for women (but the difference was not statistically significant), consistent with results of a recent pooled analysis of data from seven prospective studies of metachronous colorectal adenomas (19
) and of meta-analyses of prospective studies of colorectal cancer (13
). As we have discussed in detail elsewhere (20
), this risk attenuation for women may be due to the protective effect of estrogenic precursors that are produced by adipose tissue in counterbalancing the otherwise risk-enhancing properties of obesity. Alternatively, it is possible that BMI might be less associated with central adiposity in women than in men (21
), and several studies suggest that for both sexes, central adiposity is more strongly associated with colorectal cancer risk than BMI (22
). We cannot address this issue directly because we did not collect data on waist circumference (a common measure of central adiposity in population-based studies).
We found that BMI at age 20 years and adult weight gain were associated with the risk of colorectal cancer in men and women combined. The categorical sex-specific analyses suggested that adult weight gain is associated with colorectal cancer risk for men but not women. However, when modeled continuously, adult weight gain was associated with colorectal cancer risk for men and for women; these results for women should be interpreted cautiously because the linear associations are inconsistent with their respective categorical associations. For men, these observations add to the relatively sparse data in the literature, suggesting that adult weight gain is associated with an increased risk of colon adenoma (24
) and colorectal cancer (20
). Given the rarity of studies on this topic for women, additional studies on the associations between adult weight gain and BMI in early adulthood with risk of colorectal cancer are warranted.
The only other study to our knowledge that examined associations between BMI and the risk of colorectal cancer by tumor MSI status (10
) reported that in men, BMI was positively associated with MSI-negative tumors but not with MSI-positive tumors (odds ratios were 1.9 [95% CI = 1.5 to 2.4] and 1.0 [95% CI = 0.6 to 1.6], respectively). We observed the same pattern of associations for men and women combined for MS-stable and MSI-high. For women, the study by Slattery et al. (10
) reported that BMI was relatively equivalently and weakly associated with the risk of MSI-negative (OR = 1.3; 95% CI = 1.0 to 1.7) and MSI-positive (OR = 1.3; 95% CI = 0.8 to 1.9) tumors. The discrepant results between this study and the study by Slattery et al. may be explained by the MSI definitions used in the two studies: This study characterized three levels of MSI (MS-stable, MSI-low, and MSI-high), whereas Slattery et al. (10
) characterized only two levels (MSI-negative and MSI-positive, which correspond to MS-stable and MSI-high, respectively, in this study). Our data also indicated that risk estimates were similar for MSI-low and MS-stable tumors, although the sample size for MSI-low was considerably smaller than MS-stable. The collective evidence from these two studies suggests that BMI is most strongly associated with the risk of MS-stable colorectal tumors; however, given the relatively small numbers of MSI-high tumors in these studies, these results might be due to chance, and future studies with larger sample sizes are needed to confirm these findings.
Several mechanisms have been proposed to explain the association between BMI, adult weight gain, and colorectal cancer risk, including insulin and the insulin-like growth factor system, adipokines (eg, leptin, adiponectin), inflammation (eg, C-reactive protein), oxidative stress, and steroid hormones, as discussed in recent comprehensive reviews (28
). Perhaps more relevant here are experimental data regarding differing associations for excess body weight and risk of MS-stable vs MSI-high tumors, including results from studies in mice (30
). For example, an obesity-causing mutation in the leptin receptor was required for the development of colon neoplasia in adenomatous polyposis coli (APC)-mutant mice (an experimental model of human adenomatous polyposis prone to MS-stable malignancies that occur predominantly in the small intestine) (30
). Mice that had the APC mutation, but lacked the leptin receptor mutation and therefore had normal body weight, developed only noncolorectal tumors (30
). An earlier study of DNA mismatch repair–deficient mice fed a high fat and low calcium diet or an energy-restricted diet suggested no effect of diet or weight change on the development of intestinal adenomas or cancers, despite marked differences in overall survival between mice fed the different diets (31
). Results of these two animal studies are in agreement with our findings of an association between recent BMI and increased risk of MS-stable tumors and no association between recent BMI and risk of MSI-high tumors. The combined evidence suggests that obesity is a strong risk factor for colorectal tumors that display the MS-stable phenotype.
The underlying basis for the increased risk of MS-stable tumors associated with overweight or obesity and the lack of an association with MSI-high tumors remain largely speculative. However, one possible explanation includes the matrix metalloproteinase system, which is involved in diet-induced obesity through remodeling of the extracellular matrix that surrounds the expanding adipose tissue (32
) and in the degradation of the extracellular matrix during colorectal cancer metastasis (33
). mRNA levels of several metalloproteinases were differentially expressed in a mouse model of diet-induced obesity (34
), and gene expression analysis has further shown that MMP-7
expression is increased in MS-stable colorectal cancer cell lines compared with non-neoplastic cell lines, but not in MSI-high cell lines compared with non-neoplastic cell lines (35
). Another potential biological source of our observations of increased risk of MS-stable tumors from overweight and obesity and no associations for risk of MSI-high tumors involves telomeres (the physical ends of chromosomes): An inverse association between telomere length and body weight was reported recently (36
), and shorter telomere length, in turn, has been linked to chromosomal instability and MS-stable colorectal tumors but not to MSI-high colorectal tumors (37
). If the differential associations for BMI and tumor MSI reported here are replicated in future studies, additional studies will be needed to better understand the differing etiologies of MS-stable and MSI-high colorectal cancers.
Limitations of this study include the use of self-reported body weight and height, along with the somewhat prolonged interval (2–5 years) between colorectal cancer diagnosis and baseline interview for some subjects (27%). A recent cross-sectional study suggested that BMI measures based on self-reports of height and weight are, on average, 1.3 kg/m2
lower than directly measured values (38
). Underreporting of self-reported BMI may overestimate associations between being overweight and the risk of colorectal cancer compared with studies that have direct measures of body weight. However, generally good-to-excellent agreement between self-reported and directly measured values of height and weight has been reported in study populations that were demographically similar to the one used in this study (39
). Furthermore, prospective studies (41
) with direct measures of height and weight reported estimates of associations between BMI and colorectal cancer risk that are similar to those reported in this study.
An additional limitation of this study is the possibility of survival bias because some potential case subjects may have died before they had the opportunity to enroll in this study. Because obesity is associated with poorer survival after diagnosis of colorectal cancer (43
), survival bias might have contributed to an underestimate of the risk of colorectal cancer associated with obesity. We would expect survival bias to have less of an impact on analyses of case subjects with MSI-high tumors because of the better survival of these patients compared with patients with MS-stable tumors (6
). The lack of association between BMI and risk of MSI-high tumors, therefore, appears unlikely to be explained by survival bias.
The strengths of this study include the large number of colorectal cancer case subjects with detailed assessments of their tumor MSI status according to standardized protocols. We also used a control series comprising unaffected same-sex siblings of the case subjects. The use of such a control group reduces potential unmeasured confounding from factors that include genetic variation and early-life exposures to potential risk factors (44
In summary, our data suggest that BMI approximately 1 year before a colorectal cancer diagnosis is associated with the risk of this disease, slightly more so for men than for women. Long-term weight status, as reflected by BMI at age 20 years and adult weight gain, is also associated with the risk of colorectal cancer. Our data also suggest that the associations between BMI and adult weight gain and the risk of colorectal cancer differ between MS-stable and MSI-high tumors, as defined by the Bethesda panel, further suggesting differing underlying etiologies for colorectal cancer according to tumor MSI.