Colorectal cancer is a leading cause of cancer morbidity and mortality worldwide. Epidemiologic studies have identified a host of genetic, lifestyle and demographic factors associated with colorectal cancer incidence, including high body mass index (BMI) and, perhaps less convincingly, cigarette smoking. Epidemiologic studies have often considered colorectal cancer as a singular disease outcome, ignoring potential disease heterogeneity; more recently, however, studies have further investigated whether risk and prognostic factors for colorectal cancer differ by tumor molecular phenotype, including microsatellite instability (MSI) status. MSI is the result of defective DNA mismatch repair capacity and it is a distinct tumor phenotype whereby short repetitive DNA sequences undergo a change in repeat length. Approximately 15% of colorectal tumors display MSI, usually the result of epigenetic modification of MLH1, a gene that encodes a mismatch repair protein, or less often, because the affected individual has a germline mutation in a DNA mismatch repair gene, consistent with Lynch syndrome. The majority of colorectal tumors develop despite having competent mismatch repair; these tumors, known as microsatellite (MS)-stable, arise through chromosomal instability and do not display marked gains or losses in MS regions. Other important molecular phenotypes for colorectal cancer include CpG island methylator phenotype (CIMP), and presence or absence of somatic mutations in the KRAS and BRAF genes.

While BMI is a consistent and convincing risk factor for colorectal cancer overall (odds ratios and relative risks in the range of 1.3 to 1.5 are common for an obese BMI relative to a normal BMI), recent studies have suggested the associations are higher, or even restricted to, tumors that are MS-stable. Using the Colon Cancer Family Registry, our group showed that an obese BMI (>30 kg/m^2) relative to a normal BMI (BMI: 18.5-24.99 kg/m^2) was associated with an approximate 2-fold increased risk of MS-stable colorectal cancer while the association with MSI-high colorectal cancer was null. Other recent studies have shown a similar pattern, and other groups have shown that these results might be corroborated with FASN. Current work in the Colon Cancer Family Registry is seeking to address whether the prognostic (i.e., survival) benefit of MSI-high compared to MS-stable tumors further differs by level of obesity.

The link between colorectal cancer and cigarette smoking has been more equivocal, with studies generally showing null associations or only modestly higher risks among smokers compared to non-smokers. Herein, tumor molecular phenotype data have been particularly revealing. Data from the Colon Cancer Family Registry showed a null association between ever smoking and colorectal cancer risk overall; however, when stratified by MSI status, risk of MSI-high cancer was about 2-fold higher among long-duration smokers relative to never smokers. Similar findings were reported in the prospective Iowa Women's Health Study where doubling in risks of MSI-high, CIMP-positive and BRAF mutation-positive colorectal cancers were reported for ever smoking while null associations were shown for tumors that lacked these molecular phenotypes. Additional work from one study center involved in the Colon Cancer Family Registry has suggested that the adverse impact of smoking on colorectal cancer survival is limited to patients diagnosed with MSI-high tumors.

In addition to presenting published and unpublished results on associations of BMI and smoking with colorectal cancer incidence and survival, this presentation will also share recent experiences with collecting tumor blocks from a prospective cohort study, the American Cancer Society's Cancer Prevention Study-II.

Citation Format: Peter T. Campbell. Insight into colorectal cancer etiology through MPE: Unmasking the links with obesity and smoking. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN06-02.