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Int. J. Environ. Res. Public Health 2017, 14(10), 1146;

Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival

School of Public Health, University of Alberta, Edmonton, AB T6G 2R3, Canada
Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA
Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612, USA
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195, USA
Centre for Public Health Research, Massey University, P.O. Box 756, Wellington 6140, New Zealand
Department of Epidemiology & Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Authors to whom correspondence should be addressed.
Received: 30 July 2017 / Revised: 6 September 2017 / Accepted: 23 September 2017 / Published: 28 September 2017
(This article belongs to the Special Issue Gene-Environment Interactions and Disease)
Full-Text   |   PDF [530 KB, uploaded 28 September 2017]   |  


Characterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes. View Full-Text
Keywords: angiogenesis; candidate gene-pathway; gene-environment interactions; rectal cancer; cancer risk; cancer survival angiogenesis; candidate gene-pathway; gene-environment interactions; rectal cancer; cancer risk; cancer survival

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Sharafeldin, N.; Slattery, M.L.; Liu, Q.; Franco-Villalobos, C.; Caan, B.J.; Potter, J.D.; Yasui, Y. Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival. Int. J. Environ. Res. Public Health 2017, 14, 1146.

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