Lifestyle Factors and Microsatellite Instability in Colorectal Cancer: The Evolving Field of Molecular Pathological Epidemiology

Colorectal cancer is not a single disease. It encompasses heterogeneous diseases with different sets of genetic and epigenetic alterations. Each tumor arises and behaves in a unique fashion that is unlikely to be exactly recapitulated by any other tumor (1). Nevertheless, we classify colorectal cancers into a limited number of groups (eg, microsatellite instability MSI-high vs microsatellite stability MSS) because we assume that tumors with similar characteristics have arisen through common mechanisms and behave in a similar fashion (1). Traditional epidemiology research has typically investigated factors that are associated with the overall risk of colorectal cancer, although distinct risk factors have long been recognized for colon and rectal cancers. Traditional pathology research has explored histopathologic and molecular characteristics to predict prognosis and response to specific treatment (2). More recently, these two approaches have converged to improve our understanding of how particular exposures influence carcinogenesis by examining molecular pathological marks of tumor initiation or progression, in relation to exposures of interest, for both etiology (3–27) and prognosis (28–34). These new research efforts can be thought of as molecular pathological epidemiology, a multidisciplinary investigation of the interrelationships between exogenous and endogenous (eg, germline genetic) factors, tumor molecular signatures, and tumor initiation, progression, and response to treatment. In this issue of Journal, Campbell et al. (35) describe a case– control study of body mass index (BMI) and colorectal cancer risk in relation to tumor MSI status. As others have found (36,37), the authors showed that prediagnosis BMI was associated with an increased risk of colorectal cancer. In addition, they showed that this excess risk was limited to MSS tumors (for a BMI increment of 5 kg/m2, adjusted odds ratio = 1.38, 95% confidence interval = 1.24 to 1.54); BMI was not associated with the risk of MSI-high tumors (adjusted odds ratio = 1.05; 95% confidence interval = 0.84 to 1.31). Two previous case–control studies have examined the relationship between BMI and colon cancer risk by MSI status (5,10). Slattery et al. (5) examined 118 MSI-high and 696 MSS tumors and found that high BMI was associated with the risk of MSS tumors but not with the risk of MSI-high tumors among men; they observed no such difference in women. Satia et al. (10) examined 49 MSI-high and 437 MSI-low or MSS tumors and found that high BMI before diagnosis was associated with the risk of MSI-low or MSS tumors but not with the risk of MSI-high tumors. These results are generally consistent with those of Campbell et al. (35), providing further evidence for the specific relationship between obesity and the risk of MSS cancer. The specificity of this link not only reinforces a causal interpretation but also points the way to a specific mechanism. Experimental evidence supports the link between obesity and