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Published online first on February 26, 2013
[Cancer Research, 10.1158/0008-5472.CAN-12-2276]
© 2013 American Association for Cancer Research
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Prevention and Epidemiology

Prospective Analysis of Body Mass Index, Physical Activity, and Colorectal Cancer Risk Associated with β-Catenin (CTNNB1) Status

Teppei Morikawa1, Aya Kuchiba1, Paul Lochhead1, Reiko Nishihara1, Mai Yamauchi1, Yu Imamura1, Xiaoyun Liao1, Zhi Rong Qian1, Kimmie Ng1, Andrew T. Chan2,4, Jeffrey A. Meyerhardt1, Edward Giovannucci2,5,6, Charles S. Fuchs1,2, and Shuji Ogino1,3,5

Authors' Affiliations: 1 Department of Medical Oncology, Dana-Farber Cancer Institute; 2 Channing Division of Network Medicine, Department of Medicine; 3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; 4 Gastrointestinal Unit, Massachusetts General Hospital; Departments of 5 Epidemiology and 6 Nutrition, Harvard School of Public Health, Boston, Massachusetts

Corresponding Author: Shuji Ogino, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Room M422, Boston, MA 02215. Phone: 617-632-1972; Fax: 617-582-8558; E-mail: shuji_ogino{at}dfci.harvard.edu

Dysregulation of the WNT/β-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses' Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18–1.53 for 5.0 kg/m2 increment; Ptrend = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92–1.25 for 5.0 kg/m2 increment; Ptrend = 0.36; Pheterogeneity = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87–1.00 for 10 MET-h/wk increment; Ptrend = 0.044) but not with CTNNB1-positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91–1.05 for 10 MET-h/wk increment; Ptrend = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. Cancer Res; 73(5); 1–11. ©2013 AACR.




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H. Nan, T. Morikawa, M. Suuriniemi, Y. Imamura, L. Werner, A. Kuchiba, M. Yamauchi, D. J. Hunter, P. Kraft, E. L. Giovannucci, et al.
Aspirin Use, 8q24 Single Nucleotide Polymorphism rs6983267, and Colorectal Cancer According to CTNNB1 Alterations
J Natl Cancer Inst, December 18, 2013; 105(24): 1852 - 1861.
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