Journal
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
Volume 14, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijerph14101146
Keywords
angiogenesis; candidate gene-pathway; gene-environment interactions; rectal cancer; cancer risk; cancer survival
Funding
- Canadian Institutes of Health Research
- NCI [CA48998, CA615757]
- Utah Cancer Registry - National Cancer Institute [N01-PC-67000]
- State of Utah Department of Health
- Northern California Cancer Registry
- Sacramento Tumor Registry
- Canada Research Chair Program
- Alberta Innovates-Health Solutions
- Alberta Cancer Foundation
- University of Alberta Dissertation Fellowship
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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.
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