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Genetic variation in the transforming growth factor-?-signaling pathway, lifestyle factors, and risk of colon or rectal cancer.

ABSTRACT: The transforming growth factor-?-signaling pathway has been identified as being involved in colorectal cancer.The aim of this study was to determine how diet and lifestyle factors in combination with genetic variation in the transforming growth factor-?-signaling pathway alters colorectal cancer risk.We used data from 2 population-based case-control studies.Participants included patients with colon cancer (n = 1574) and controls (n = 1970) and patients with rectal cancer ( n = 791) and controls (n = 999).The primary outcomes measured were newly diagnosed cases of colon or rectal cancer.Colon and rectal cancer risk increased with the number of at-risk genotypes within the transforming growth factor-?-signaling pathway (OR 3.68, 95% CI 2.74,4.94 for colon cancer; OR 3.89, 95% CI 2.66,5.69 for rectal cancer). A high at-risk lifestyle score also resulted in significant increased risk with number of at-risk lifestyle factors (OR 2.99, 95% CI 2.32,3.85 for colon cancer; OR 3.37, 95% CI 2.24,5.07 for rectal cancer). The combination of high-risk genotype and high-risk lifestyle results in the greatest increase in risk (OR 7.89, 95% CI 4.45,13.96 for colon cancer; OR 8.75, 95% CI 3.66,20.89 for rectal cancer).The study results need validation in other large studies of colon and rectal cancer.In summary, our data suggest that there is increased colon and rectal cancer risk with increasing number of at-risk genotypes and at-risk lifestyle factors. Although the integrity of the pathway can be diminished by a number of high-risk genotypes, this risk can be offset, in part, by maintaining a healthy lifestyle.

SUBMITTER: Slattery ML

PROVIDER: S-EPMC3652588 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genetic variation in the transforming growth factor-β-signaling pathway, lifestyle factors, and risk of colon or rectal cancer.

Slattery Martha L ML Lundgreen Abbie A Wolff Roger K RK Herrick Jennifer S JS Caan Bette J BJ

Diseases of the colon and rectum 20120501 5

<h4>Background</h4>The transforming growth factor-β-signaling pathway has been identified as being involved in colorectal cancer.<h4>Objective</h4>The aim of this study was to determine how diet and lifestyle factors in combination with genetic variation in the transforming growth factor-β-signaling pathway alters colorectal cancer risk.<h4>Design</h4>We used data from 2 population-based case-control studies.<h4>Patients</h4>Participants included patients with colon cancer (n = 1574) and control ...[more]

PMID: 22513431

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Project description:BackgroundThe transforming growth factor-β (TGF-β) signaling pathway is involved in many aspects of tumorigenesis, including angiogenesis and metastasis. The authors evaluated this pathway in association with survival after a diagnosis of colon or rectal cancer.MethodsThe study included 1553 patients with colon cancer and 754 patients with rectal cancer who had incident first primary disease and were followed for a minimum of 7 years after diagnosis. Genetic variations were evaluated in the genes TGF-β1 (2 single nucleotide polymorphisms [SNPs]), TGF-β receptor 1 (TGF-βR1) (3 SNPs), smooth muscle actin/mothers against decapentaplegic homolog 1 (Smad1) (5 SNPs), Smad2 (4 SNPs), Smad3 (37 SNPs), Smad4 (2 SNPs), Smad7 (11 SNPs), bone morphogenetic protein 1 (BMP1) (11 SNPs), BMP2 (5 SNPs), BMP4 (3 SNPs), bone morphogenetic protein receptor 1A (BMPR1A) (9 SNPs), BMPR1B (21 SNPs), BMPR2 (11 SNPs), growth differentiation factor 10 (GDF10) (7 SNPs), Runt-related transcription factor 1 (RUNX1) (40 SNPs), RUNX2 (19 SNPs), RUNX3 (9 SNPs), eukaryotic translation initiation factor 4E (eiF4E) (3 SNPs), eukaryotic translation initiation factor 4E-binding protein 3 (eiF4EBP2) (2 SNPs), eiF4EBP3 (2 SNPs), and mitogen-activated protein kinase 1 (MAPK1) (6 SNPs).ResultsAfter adjusting for American Joint Committee on Cancer stage and tumor molecular phenotype, 12 genes and 18 SNPs were associated with survival in patients with colon cancer, and 7 genes and 15 tagSNPs were associated with survival after a diagnosis of rectal cancer. A summary score based on "at-risk" genotypes revealed a hazard rate ratio of 5.10 (95% confidence interval, 2.56-10.15) for the group with the greatest number of "at-risk" genotypes; for rectal cancer, the hazard rate ratio was 6.03 (95% confidence interval, 2.83-12.75).ConclusionsThe current findings suggest that the presence of several higher risk alleles in the TGF-β signaling pathway increase the likelihood of dying after a diagnosis of colon or rectal cancer.

Project description:BackgroundAssociations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process.MethodsWe used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls) and rectal (n = 754 cases, 959 controls) cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH), SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk.ResultsAfter adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208). Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300). Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR) and rectal cancer (SepX1 increased HRR).ConclusionsFindings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is modified by lifestyle.

Dataset Information

Genetic variation in the transforming growth factor-?-signaling pathway, lifestyle factors, and risk of colon or rectal cancer.

Publications

Genetic variation in the transforming growth factor-β-signaling pathway, lifestyle factors, and risk of colon or rectal cancer.

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