Marty L. Slattery

Body size and the risk of colon cancer in a large case-control study.

OBJECTIVE: To investigate the risks of height, weight and body fat distribution associated with colon cancer in subcategories of gender, age and site in the colon. Interaction with family history of colorectal cancer is also examined.DESIGN: Case- control study of diet, anthropometry and colon cancer risk.SUBJECTS: Nineteen hundred and eighty-three colon cancer cases (age 30–79 y) and 2400 age and gender matched population controls.MEASUREMENTS: Height, weight and waist and hip circumferences were obtained by trained interviewers. Body Mass Index (BMI) and Waist-Hip Ratio (WHR) were calculated.RESULTS: Of all anthropometric measurements examined, only BMI was consistently associated with an increased risk of colon cancer. The test for trend for BMI was significant for men and women overall and for the majority of subgroups examined. In younger persons those with a family history of colorectal cancer had a greater risk of colon cancer associated with BMI (Men odds ratio (OR)=7.76, 95% confidence interval (CI) 2.60, 23.1; Women OR=4.85, 95% CI 2.33, 10.12) comparing the third tertile to the first, than those with no family history (Men OR=1.70 95% CI 1.25, 2.32; Women OR=1.53 95% CI 1.22, 1.92). WHR, after controlling for BMI was not associated with colon cancer in men, and was associated with a slight increase in women (primarily in those with distal tumors).CONCLUSION: This study contributes to mounting evidence that excess weight is associated with an increased risk of colon cancer.

Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States)

Objective: The association between body mass index (BMI) and colon cancer has been reported to be different for men and women. No prior literature has examined if estrogen influences these differences. Methods: Using data from an incident population-based case (n = 1972) and control (n = 2386) study of colon cancer we evaluated if estrogen modifies the association between BMI and risk of colon cancer. Results: Women who were estrogen-negative (postmenopausal women not taking hormone replacement therapy, HRT) were at increased risk of colon cancer regardless of indicator of estrogen status used (i.e. estrogen-negative compared to estrogen-positive women defined as either being premenopausal or postmenopausal women using HRT, OR 1.54, 95% CI 1.23–1.93; no recent exposure to estrogens compared to current or HRT use within the past 2 years, OR 1.58, 95% CI 1.24–2.00; postmenopausal women not currently using HRT compared to postmenopausal women taking HRT, OR 1.65, 95% CI 1.29–2.12). BMI (kg/m2) was not associated with an increased risk of colon cancer among women who were estrogen-negative. However, women who were estrogen-positive experienced a greater than two-fold increase in colon cancer risk if they had a BMI of > 30 relative to those who had a BMI of <23 (for estrogen-positive, OR, 2.50, 95% CI 1.51–4.13; premenopausal, OR 2.19, 95% CI 0.94–5.07; postmenopausal using HRT, OR 3.36, 95% CI 1.58–7.13). Among men the colon cancer risk associated with BMI decreased with advancing age. Physical activity modified the increased colon cancer risk associated with a large BMI. Conclusions: These data suggest the importance of estrogen in colon cancer etiology. Being estrogen-negative resulted in a significant increased risk of colon cancer. However, BMI significantly increased the risk of colon cancer among women who were estrogen-positive. We hypothesize that estrogen up-regulates IGF-I receptors and IRS-I levels in the colon, which in turn increases susceptibility to obesity-induced increased levels of insulin. We further hypothesize that androgens may have similar effects in men given the decline in colon cancer risk associated with BMI with advancing age.

Family history and colorectal cancer: predictors of risk.

Introduction: While the association between family history of colorectal cancer in first-degree relatives and risk of developing colon cancer has been well defined, the association with rectal cancer is much less clear. The purpose of this study is to define rectal cancer risk associated with family history of colorectal cancer in first-degree relatives. We also evaluate diet and lifestyle factors associated with developing colorectal cancer among participants with a positive family history. Methods: Data were available from two population-based case–control studies of colon and rectal cancer. Participants were members of the Kaiser Permanente Medical Care Program (KPMCP) or residents of the state of Utah. Cases were first primary colon cancer diagnosed between 1991 and 1994 (n = 1308 cases and 1544 controls) or rectal cancer diagnosed between 1997 and 2001 (n = 952 cases and 1205 controls). Results: A family history of colorectal cancer in any first-degree relatives slightly increased risk of rectal cancer (OR: 1.37 95% CI: 1.02–1.85). Family history of colorectal cancer was associated with the greatest risk among those diagnosed at age 50 or younger (OR: 2.09 95% CI: 0.94–4.65 for rectal tumors; OR: 3.00 95% CI: 0.98–9.20 for distal colon tumors; and OR: 7.88 95% CI: 2.62–23.7 for proximal colon tumors). Factors significantly associated with cancer risk among those with a family history of colorectal cancer, included not having a sigmoidoscopy (OR: 2.81 95% CI: 1.86–4.24); a diet not Prudent, i.e. high in fruits, vegetables, whole grains, fish and poultry, (OR: 2.79 95% CI: 1.40–5.56); smoking cigarettes (OR: 1.68 95% CI: 1.12–2.53), and eating a Western diet, i.e. a diet high in meat, refined grains, high-fat foods, and fast foods, (OR: 2.15 95% CI: 1.06–4.35). Physical inactivity was not associated with increased cancer risk among those with a positive family history of colorectal cancer. Summary: These results confirm observations reported by others that a family history of colorectal cancer increases risk of cancer among those diagnosed at a younger age. Associations with family history are weakest for rectal cancer and strongest for proximal colonic tumors. Since several diet and lifestyle factors influence development of cancer among those with a family history of the disease, there appears to be practical approaches for individuals with a family history of colorectal cancer to reduce their cancer risk.

The Polyp Prevention Trial–Continued Follow-up Study: No Effect of a Low-Fat, High-Fiber, High-Fruit, and -Vegetable Diet on Adenoma Recurrence Eight Years after Randomization

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745–52)

GSTM-1 and NAT2 and genetic alterations in colon tumors

Objective: Phase II metabolizing enzymes such as glutathione S-transferases and N-acetyltransferase are involved in the detoxification of carcinogens. Genetic variants of genes coding for these enzymes have been evaluated as to their association with colon cancer, both as independent risk factors and as effect modifiers for associations with diet and cigarette smoking. In this study, we evaluate associations between the GSTM-1 genotype and the NAT2-imputed phenotype and acquired mutations in tumors Methods: Data is taken from a set of 1836 cases and 1958 controls with colon cancer who were part of a large case–control study of colon cancer and whose tumors were previously analyzed for Ki-ras, p53, and microsatellite instability (MSI). We also evaluate the modifying effects of these genetic variants with diet and cigarette smoking, factors previously identified as being associated with specific tumor alterations. Results: Neither GSTM-1 nor the NAT2-imputed phenotype was independently associated with Ki-ras, p53, or MSI. Cigarette smoking significantly increased the risk of tumors involving the MSI pathway. Additionally, cigarette smoking doubled the risk of p53 transversion mutations among those who were GSTM-1 present. Cases were slightly more likely to have a p53 mutation if they frequently consumed red meat and had the imputed NAT2 intermediate/rapid phenotype relative to slow phenotype/infrequent consumers of red meat (OR 2.0, 95% CI 1.3–3.0 for intermediate/rapid). Conclusions: These data provide support that diet and cigarette smoking may be associated with specific disease pathways, although GSTM-1 and NAT2 do not independently appear to alter susceptibility to these diet and lifestyle factors.

Abstract 4489: Using functional data from Roadmap Epigenomics to inform analysis of rare variants linked to gene expression in a large colorectal cancer study

To investigate the role of low frequency and rare genetic variation in colorectal cancer (CRC) susceptibility, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR) conducted whole genome sequencing and imputed into genome-wide association studies (GWAS) of 14,718 CRC cases and 12,186 controls. These data provide a unique opportunity to investigate rare variants, which contribute to the majority of the variation in the genome. To improve power for discovering rare CRC susceptibility variants ( Citation Format: Stephanie A. Bien, Tabitha A. Harrison, Paul L. Auer, Flora Qu, Jeroen Huyghe, Barbara Banbury, Peyton Greenside, Goncalo R. Abecasis, Sonja I. Berndt, Stephane Bezieau, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Sai Chen, Joshua D. Smith, Loic Le Marchand, Christopher Carlson, Polly A. Newcomb, Christian Fuchsberger, Marty L. Slattery, Hyun M. Kang, Emily White, John Potter, Steven J. Gallinger, Michael Hoffmeister, Stephen B. Gruber, Deborah A. Nickerson, Ulrike Peters, Anshul Kundaje, Li Hsu. Using functional data from Roadmap Epigenomics to inform analysis of rare variants linked to gene expression in a large colorectal cancer study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4489.

Abstract B62: Beta-2 adrenergic receptor polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: The 4-Corners Breast Cancer Study

Polymorphisms in the adrenergic receptor beta-2 (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, but few studies have investigated associations with breast cancer. The purpose of this research was to evaluate the hypothesis that ADRB2 variants (rs1042713-Arg16Gly and rs1042714-Glu27Gln) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case-control study conducted in the southwestern United States: ‘The 4-Corners Breast Cancer Study’. A total of 1,244 NHW and 606 H cases with incident primary breast were ascertained and 1,330 NHW and 728 H population-based controls were selected. Information on lifestyle and physical activity, diet, demographics, and reproductive background was collected through an in-person questionnaire, and blood samples were taken for genetic analyses from consenting participants. ADRB2 genotypes for rs1042713 and rs1042714 were determined using PCR. Each genotype as well as their combined haplotype was evaluated in multivariable logistic regression models to estimate the associations with breast cancer risk while adjusting for potential confounders, including study center, history of diabetes, body mass index, family history of breast cancer, genetic admixture, and menopausal status. ADRB2 genotype frequencies were significantly different between NHW and H women. Individually, the ADRB2 polymorphisms were not associated with breast cancer in either ethnic group. However, having 2 copies compared to one or zero copies of the ADRB2 G-G haplotype was associated significantly with increased risk of breast cancer among NHW women [odds ratio (OR), 1.95; 95% confidence interval (95% CI), 1.26–3.01] but reduced risk among Hispanic women [OR, 0.74; 95% CI, 0.50–1.09], (p-for interaction=0.004). Risk was significantly decreased in Hispanic women with a history of type 2 diabetes and 2 copies of the G-G haplotype [OR, 0.33; 95% CI, 0.12–0.92] while the association was increased, but not statistically significant among NHW women, [OR, 4.91; 95% CI, 0.52–46.60], (p-for interaction = 0.025). While the interaction between obesity (body mass index (BMI) ≥ 30 kg/m2) and the G-G haplotype was not significant (p=0.200), the association in NHW obese women with 2 copies of the G-G haplotype was similarly increased [OR, 3.01; 95% CI, 1.22–7.44], but decreased in Hispanics [OR, 0.42; 95% CI, 0.20–0.56]. These data suggest that ethnicity modifies the association between the ADRB2 G-G haplotype and breast cancer risk and history of type 2 diabetes and obesity enhances the divergence of risk between Hispanic and NHW women. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B62.

Abstract 5710: COX-1 and COX-2 polymorphisms, NSAID use, and the risk of colorectal neoplasia

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk of colorectal adenomas and cancer. NSAIDs, including aspirin, target the prostaglandin H synthases, COX-1 and COX-2, which convert arachidonic acid into prostaglandins. We examined tagSNPs and candidate polymorphisms in COX-1 and COX-2 in relation to colorectal neoplasia risk and potential interactions with NSAID use. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in PTGS1 (COX-1) and PTGS2 (COX-2) representative of common genetic variation in Europeans. Including candidate polymorphisms, we genotyped 18 SNPs in PTGS1 and 17 SNPs in PTGS2. SNPs were genotyped on the same Illumina platform in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma and cancer cases. We investigated these SNPs in relation to the risk of colorectal neoplasia and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424) vs. controls (n=1780), rectal cancer (n=583) vs. controls (n=775), and colorectal adenoma (n=485) vs. controls (n=578). For single SNP associations, multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study populations). No correction was made for multiple testing. Results: There were no main associations with PTGS1 tagSNPs or candidate polymorphisms (R8W, P17L and L237M) and colorectal neoplasia risk. Although not statistically significant, the L15-L16 deletion allele showed a trend towards increased risk for both colon and rectal cancer, consistent with the previously reported increased adenoma risk. In PTGS2, a rare 5′ tagSNP (rs4648250, −1877A>G, MAF=1%) was associated with a marginally decreased risk of both rectal (OR: 0.24, 95% CI: 0.05-1.08) and colon cancer (OR: 0.63, 95% CI: 0.36-1.10). NSAID use is known to reduce the risk of colorectal neoplasia and all three studies have shown the same protective effect in previous analyses. Interactions between genotypes and NSAID use essentially fell into one of two general categories: a) Individuals with the variant allele lost the protective effect of NSAID use (PTGS1 rs10306110-G, rectal p-interaction=0.02, adenoma p-int=0.08; PTGS2 [rs689466][1]-G, rectal p-int=0.03, colon p-int=0.18; rs20424-G, colon p-int=0.05; [rs689469][2]-A, colon p-int=0.03, rectal p-int=0.09).); and b) Individuals with the variant allele showed stronger protection with by NSAIDs than individuals with the wildtype genotype (PTGS1 rs6478565-G, rs10306135-T, rs10306164-G, rectal p-int=0.01-0.02). Conclusion: These data suggest that a rare 5′ SNP in PTGS2 may predict risk of colorectal cancer and provide further evidence that genetic variability in PTGS1 and PTGS2 may modify the protective association between NSAID and colorectal neoplasia risk, especially for rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5710. [1]: /lookup/external-ref?link_type=GEN&access_num=rs689466&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs689469&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom

Abstract 934: Phospholipase A2A polymorphisms and risk of colorectal neoplasia: Table.

Introduction: Pancreatic phospholipase A2 (also known as PLA2G1B or PLA2A) catalyzes the release of fatty acids from dietary phospholipids for adsorption in the small intestine. Some of the polyunsaturated fatty acids removed from the intestinal lumen are precursors to eicosanoids, which are linked to inflammation, cell proliferation and colorectal carcinogenesis. We suspect that genetic variation at the PLA2A locus might affect colorectal neoplasia and thus we evaluated the association of PLA2A tagSNPs with colorectal neoplasia risk in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r 2 =0.90, MAF=4%) identified 3 tagSNPs in PLA2A. We genotyped these SNPs on the same Illumina platform in 3 US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). LD was calculated among Caucasian controls for each study. For gene-level associations, we conducted principal components analysis (PCA) and haplotype analysis. Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: Two PLA2A variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702G>A Ser98Ser, p-trend = 0.03 and rs9657930, 1593C>T p-trend = 0.01, see table). Linkage disequilibrium between the SNPs was modest (r 2 Conclusion: The results suggest that genetic variability in PLA2A affects susceptibility to rectal but not colon cancer. Additional observational and functional follow-up studies are needed. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 934.

Abstract 933: Glutathione peroxidase (GPX) candidate and tagSNPs and risk of colorectal neoplasia: Table.

Introduction: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that scavenge hydroperoxides linked to oxidative stress, prostaglandin synthesis, inflammation and proliferation. Because these processes are important in carcinogenesis, we hypothesized that genetic variability in the GPXs may influence colorectal neoplasia risk. We investigated candidate polymorphisms and tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 24 tagSNPs, including the candidates (GPX1 P200L and GPX4 2573 C>T), representing common genetic variation in Europeans. We used an identical Illumina platform to investigate GPX SNPs in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal components analysis (PCA). Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: In PCA, GPX3 was significant for rectal cancer at p=0.03. Without correction for multiple testing, five polymorphisms in GPX2 and GPX3 were associated with significant differences in rectal cancer risk at α=0.05 (see Table). GPX3 rs8177406 also reduced risk in rectal polyps. The candidate GPX1 P200L showed a marginally increased risk for LP/LL vs. PP (1.22, 0.98-1.52, p=0.06). No other SNPs in GPX1-4 showed significant associations for rectal cancer or adenomas. No associations were observed for colon cancer. Conclusion: These data provide evidence that genetic variability in GPX2 and GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for unique etiological mechanisms for colon and rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 933.