Dataset Information

Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk.

ABSTRACT: MicroRNAs (miRNA) can act as oncogenes or tumor suppressors and modulate the expression of approximately one third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single nucleotide polymorphisms (SNP) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequency-matched (age, gender, and ethnicity) controls. Seven SNPs were significantly associated with esophageal cancer risk. The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 [95% confidence interval (95% CI), 0.51-0.80; P for trend < 0.0001]. This association remained significant after we corrected for multiple comparisons. A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio, 0.65; 95% CI, 0.42-0.99). We did a combined unfavorable genotype analysis to further evaluate the cumulative effects of the promising (risk associated) SNPs. In comparison with the low-risk group (fewer than three unfavorable genotypes), the medium-risk group (three unfavorable genotypes) had a 2.00-fold (95% CI, 1.31-3.08) increased risk and the high-risk group (more than three unfavorable genotypes) had a 3.14-fold (95% CI, 2.03-4.85) increased risk (P for trend < 0.0001). Results for the risk of esophageal adenocarcinoma were similar to the overall risk results. The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.

SUBMITTER: Ye Y

PROVIDER: S-EPMC2768267 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk.

Ye Yuanqing Y Wang Kenneth K KK Gu Jian J Yang Hushan H Lin Jie J Ajani Jaffer A JA Wu Xifeng X

Cancer prevention research (Philadelphia, Pa.) 20081101 6

MicroRNAs (miRNA) can act as oncogenes or tumor suppressors and modulate the expression of approximately one third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single nucleotide polymorphisms (SNP) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal cancer patients (85.5% with esophageal adenocar ...[more]

PMID: 19138993

Similar Datasets

Project description:BackgroundCancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility.Patients and methodsWe comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed.ResultsWe found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes.ConclusionThis study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

Project description:BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Project description:Background & aimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Dataset Information

Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk.

Publications

Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets