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Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.

ABSTRACT: How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene-environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08-2.58 times [interaction odds ratio (ORi)=2.08-2.58, adjusted P-value (Padj)=0.02-0.04]. Compared with patients carrying ?1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi=1.89, Padj=0.016) or ?3 (ORi=4.30, Padj<0.0001) risk genotypes. Compared with cases with ?1 risk genotype, smoking-associated EA risk increased by 3.15 times when ?2 risk genotypes were present (ORi=3.15, Padj<0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.

SUBMITTER: Wu IC

PROVIDER: S-EPMC3066416 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.

Wu I-Chen IC Zhao Yang Y Zhai Rihong R Liu Chen-yu CY Chen Feng F Ter-Minassian Monica M Asomaning Kofi K Su Li L Heist Rebecca S RS Kulke Matthew H MH Liu Geoffrey G Christiani David C DC

Carcinogenesis 20110106 4

How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we us ...[more]

PMID: 21212151

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Project description:BACKGROUND:Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear. METHODS:By using a case-only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene-environment interactions were assessed by a 2-step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case-only logistic regression to assess the effects of gene-environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false-discovery rate. RESULTS:Random forest analyses identified 3 sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false-discovery rates ?0.10). Moreover, these interactions tended to have SNP dose-response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes. CONCLUSIONS:These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose-response manner.

Project description:BACKGROUND & AIMS:Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS:We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS:For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION:The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Project description:Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) develops as a result of complex epigenetic, genetic and environmental interactions. Epigenetic changes like, promoter hypermethylation of multiple tumour suppressor genes are frequent events in cancer, and certain habit-related carcinogens are thought to be capable of inducing aberrant methylation. However, the effects of environmental carcinogens depend upon the level of metabolism by carcinogen metabolizing enzymes. As such key interactions between habits related factors and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of genes are likely. However, this remains largely unexplored in ESCC. Here, we studied the interaction of various habits related factors and polymorphism of GSTM1/GSTT1 genes towards inducing promoter hypermethylation of multiple tumour suppressor genes.Methodology/principal findingsThe study included 112 ESCC cases and 130 age and gender matched controls. Conditional logistic regression was used to calculate odds ratios (OR) and multifactor dimensionality reduction (MDR) was used to explore high order interactions. Tobacco chewing and smoking were the major individual risk factors of ESCC after adjusting for all potential confounding factors. With regards to methylation status, significantly higher methylation frequencies were observed in tobacco chewers than non chewers for all the four genes under study (p<0.01). In logistic regression analysis, betel quid chewing, alcohol consumption and null GSTT1 genotypes imparted maximum risk for ESCC without promoter hypermethylation. Whereas, tobacco chewing, smoking and GSTT1 null variants were the most important risk factors for ESCC with promoter hypermethylation. MDR analysis revealed two predictor models for ESCC with promoter hypermethylation (Tobacco chewing/Smoking/Betel quid chewing/GSTT1 null) and ESCC without promoter hypermethylation (Betel quid chewing/Alcohol/GSTT1) with TBA of 0.69 and 0.75 respectively and CVC of 10/10 in both models.ConclusionOur study identified a possible interaction between tobacco consumption and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of tumour suppressor genes in ESCC.

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Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.

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Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.

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