Energy balance, insulin-related genes and risk of colon and rectal cancer Martha L. Slattery 1 * , Maureen Murtaugh 1 , Bette Caan 2 , Khe Ni Ma 1 , Susan Neuhausen 3 and Wade Samowitz 3 1 Health Research Center, University of Utah, Salt Lake City, UT, USA 2 Kaiser Permanente Medical Research Program, Oakland, CA, USA 3 Department of Internal Medicine, University of California, Irvine, CA, USA 4 Department of Surgical Pathology, University of Utah, Salt Lake City, UT, USA Energy balance, or the ability to maintain body weight by balanc- ing energy intake with energy expenditure, appears to be impor- tant in the etiology of colon cancer. One possible mechanism whereby energy balance may be associated with colorectal cancer is through its association with insulin. In our study, we evaluate the interaction between polymorphisms in 4 genes thought to be involved in insulin-related functions and components of energy balance with risk of colorectal cancer. Data from 2 population- based case-control studies of colon and rectal cancer conducted in Utah and Northern California were used to evaluate associations between body mass index (BMI), physical activity, energy intake and sucrose-to-fiber ratio and a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the G972R polymorphism of the IRS1 gene and the G1057D polymorphism of the IRS2 gene. A total of 1,346 incident colon cancer cases and 1,544 population-based controls and 952 incident rectal cancer cases and 1,205 controls were available for analysis. Inconsistent associations were identified between BMI, physical activity, energy intake and insulin-related genes. The 192/192 IGF1 genotype was associated with significant reduction in colon cancer risk among those with high physical activity (odds ratio [OR] 0.57; 95% confidence interval [CI] 0.39–0.83; p inter- action 0.01). Although there was no significant pattern of inter- action between either BMI or energy intake and polymorphisms assessed, specific sources of energy did appear to be more related to colon cancer risk in the presence of specific IRS2 and IGF1 gen- otypes. A high sucrose-to-fiber ratio increased risk of colon cancer in men who had the IRS2 DD genotype and among men who did not have the 192/192 IGF1 genotype. In summary, these data sup- port the importance of components of energy balance in risk of colorectal cancer. Obesity, physical activity and energy intake appear to alter risk of colorectal cancer; however, the risk appears to be minimally influenced by genetic variants evaluated. ' 2005 Wiley-Liss, Inc. Key words: body mass index (BMI); colorectal cancer; diet; IGF1; IGFBP3; IRS1; IRS2; physical activity Energy balance is gaining momentum as an etiologic agent of cancer. 1,2 The concept of energy balance, or the ability to main- tain body weight by balancing energy intake with energy expendi- ture, ties together important colon cancer risk factors. Several studies have detected an increased risk of colon cancer associated with increasing body mass index (BMI) primarily among men; 3–6 physical activity has been shown consistently to reduce risk of colon cancer; 7–9 and energy intake is inconsistently associated with colon cancer. 10–12 Animal studies show that restricting energy intake reduces tumor development, 13–15 supporting associa- tions detected in some case-control studies. 16–18 Data on the com- ponents of energy balance on rectal cancer are less clear. Most studies do not show obesity as being a risk factor for rectal cancer, 19,20 although some studies suggest that physical activity may reduce rectal cancer risk and energy intake may increase risk. 19,21–24 It has been proposed that energy balance may work through endo- genous hormone metabolism. 25 Of particular interest is how energy balance relates to insulin and insulin-like growth factors (IGF). 2,25 Insulin-like growth factor 1 (IGF1), insulin-like growth fac- tor-binding protein 3 (IGFBP3), insulin receptor substrate 1 (IRS1), and insulin receptor substrate 2 (IRS2) have been proposed as being involved in insulin-related pathways. Polymorphisms of these genes have been identified, some of which have been shown to have effects on insulin resistance and/or diabetes. High serum IGF-1 levels have been associated with an increased risk of colorectal cancer, and varia- tion in serum IGF-1 levels has been associated with a CA repeat polymorphism 1 kb upstream of the transcription start site. 26 This CA repeat polymorphism is denoted ‘‘192’’ for the size of the PCR product and contains 19 CA repeats. 26 In men, serum IGF-1 concen- trations were lower with the 192/192 genotype than for other IGF1 genotypes. One could predict that this genotype might be associated with a decreased risk of colorectal cancer. High levels of IGFBP-3 have been associated with a reduced risk of colorectal cancer. 27 An A/C polymorphism at nucleotide -202 is associated with different levels of IGFBP3 in a dose-response fashion, i.e., AA > AC > CC. The AC or CC genotypes would thus be predicted to be associated with an increased risk of colorectal cancer. A Gly972Arg (G972R) polymorphism in the IRS1 gene has been associated with insulin resistance and type-2 diabetes, and might be associated with an increased risk of colorectal cancer. The G1057D IRS2 polymorphism has been associated with obesity and therefore a plausible link to insulin resistance and colorectal cancer. 28 In our study, we evaluate how body size, physical activity and energy intake relate to 4 genes in the insulin pathway that are thought to be functionally important. We evaluate associations for cancers of the colon and rectum to determine site-specific effects. These analyses should provide insight into genetic susceptibility to lack of energy balance. Material and methods Study populations Participants in our study were from the Kaiser Permanente Medical Care Program of Northern California (KPMCP) and the state of Utah. Two study populations are included in these analy- ses. The first population includes cases and controls from a popu- lation-based case-control study of first primary colon cancer (ICD-O 2nd edition codes 18.0, 18.2–18.9) diagnosed from October 1, 1991 to September 30, 1994 conducted in all 3 geo- graphic areas. The second population consists of cases with a first primary tumor in the rectosigmoid junction or rectum identified from May 1997 to May 2001 in Utah and KPMCP. Case eligibility was determined by the Surveillance Epidemiology and End Results (SEER) Cancer Registries in Northern California and in Utah. In both studies, cases were identified using rapid-reporting systems. For both studies, eligibility included being from 30 to 79 years of age at time of diagnosis, English speaking, mentally com- petent to complete the interview, no previous history of colorectal cancer 16 and no known (as indicated on the pathology report) fam- ilial adenomatous polyposis, ulcerative colitis or Crohn’s disease. Controls were matched to cases by sex and by 5-year age groups. At the KPMCP, controls were randomly selected from membership *Correspondence to: Health Research Center, University of Utah, 391 Chipeta Way, Ste. A, Salt Lake City, UT 84108. Fax: þ801-581-3623. E-mail: marty.slattery@hrc.utah.edu Received 4 August 2004; Accepted after revision 26 October 2004 DOI 10.1002/ijc.20843 Published online 1 February 2005 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 115, 148–154 (2005) # 2005 Wiley-Liss, Inc. Publication of the International Union Against Cancer