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Int J Mol Epidemiol Genet 2011;2(4):328-338

Original Article
Tumor necrosis factor-related genes and colon and rectal cancer

Martha L Slattery, Abbie Lundgreen, Kristina L Bondurant, Roger K Wolff

Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; Department of
Epidemiology, Fay W Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
72205, USA.

Received August 1, 2011; accepted August 23, 2011; Epub November 15, 2011; published December 15, 2011

Abstract: Tumor necrosis factor-α (TNF) is a promoter of inflammation. Genes in the TNF pathway include tumor necrosis
factor receptor superfamily member 1A (TNFRSF1A), TNF receptor-associated factor 2 (TRAF2), mitogen activated protein
kinase 8 (MAPK8), 14 (MAPK14), and mitogen activated protein kinase kinase kinase 7 (MAP3K7), nuclear factor of activated-T-
5 (NFAT5) cells and NFAT activated protein with ITAM motif 1 (NFAM1). Data from population-based studies of colon cancer
(cases=1,555; controls=1,956) and rectal cancer (cases=754; controls=959) were used. We observed that MAP3K7
rs13208824 was associated with reduced colon cancer risk (OR 0.83, 95% CI 0.71, 0.98 dominant model), TNF rs1800630
was associated with an increased colon cancer risk (OR 1.19 95% CI 1.03, 1.38 for CA/AAvsCC), and TNFRSF1A rs4149570
was associated with reduced risk (OR 0.79 95% CI 0.64, 0.96 TTvsGG). For rectal cancer MAPK8 rs10508901 was associated
with increased risk (OR 1.45 95% CI 1.05, 1.99 AA vs CC/CA; NFAT5 (rs12447326 and rs16959025) was associated with a
40% reduced risk for the recessive model. Aspirin/NSAID interacted with MAP3K7 (colon cancer) and with MAPK14, NFAT5, and
TRAF2 (rectal cancer); smoking cigarettes interacted with NFAM1 and NFAT2 (colon cancer) and MAPK8, NFAT5, and
TNFRSF1A (rectal cancer); BMI interacted with NFAM1 and NFAT5 (colon cancer) and with MAPK8 and TNFRSF1A (rectal
cancer). A genotype summary score showed a threefold increased risk of dying with higher mutational load. Although few
independent associations were detected, aspirin/NSAID, cigarette smoking, and BMI influenced genes in this pathway. These
data suggest pathways through which TNF-signaling operates. (IJMEG1108001).

Key words: Colon cancer, rectal cancer, TNF, MAPK8, MAPK14, NFAM1, NFAT5, TRAF2, TNFRSF1A

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Address all correspondence to:
Dr. Martha L Slattery
Department of Internal Medicine
University of Utah Health Sciences Center
295 Chipeta Way, Salt Lake City, UT 84108, USA.
Tel: 801-585-6955; Fax: 801-581-3623
E-mail: marty.slattery@hsc.utah.edu