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Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

ABSTRACT: Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.84 (95% confidence interval, 0.77-0.91; P = 2.95 × 10-5 ). The rs7023329-G allele was related to a high expression of MTAP (P = 0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele odds ratio of 1.12 (95% confidence interval, 1.01-1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than non-carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50×10-5 ). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development.

SUBMITTER: Lin X

PROVIDER: S-EPMC5329157 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

Lin Xiaoming X Yan Caiwang C Gao Yong Y Du Jiangbo J Zhu Xun X Yu Fei F Huang Tongtong T Dai Juncheng J Ma Hongxia H Jiang Yue Y Yin Rong R Hu Zhibin Z Jin Guangfu G Xu Lin L Shen Hongbing H

Cancer science 20170201 2

Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 ...[more]

PMID: 27960044

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Project description:BackgroundSingle nucleotide polymorphisms (SNPs) located in microRNA (miRNA) binding sites can affect the interactions between miRNAs and target genes, which is related to cancer susceptibility and tumorigenesis. However, the association between SNPs located in miR-17-92 cluster binding sites and ESCC risk remains unclear. Therefore, we aimed to explore the relationship between polymorphisms in miR-17-92 cluster binding sites and ESCC susceptibility.MethodsSix SNPs in the binding sites of miR-17-92 cluster were selected using bioinformatics databases, and their association with ESCC risk was investigated in a case-control study (including 488 cases and 512 controls) based on the population from high incidence areas of ESCC in China. We evaluated the SNP-SNP and SNP-smoking interactions using generalized multifactor dimensionality reduction (GMDR). Moreover, the expression of the miR-17-92 cluster and its target genes was determined in ESCC and adjacent normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was conducted to verify the effect of SNPs on the binding affinity between miRNAs and target genes.ResultsWe found that the SNP rs1804506 C > T had a significant association with the decreased ESCC risk. The SNP rs1804506 T allele was associated with a significantly decreased risk of ESCC in the additive model (OR = 0.817, 95% CI = 0.681-0.981, P = 0.030). The rs1804506 T allele had more striking effects on reducing ESCC risk in older individuals, female or non-smoker subgroups. We also found a significant interaction effect between rs1366600 and smoking by GMDR methods (P = 0.011). Additionally, the expression levels of miR-19a-3p and TGFBR3 were significantly downregulated in ESCC tissues compared with normal tissues, and the carriers of rs1804506 TT genotype had lower expression level of TGFBR3 than those of rs1804506 CC/CT genotype. Following dual-luciferase reporter assay showed that the rs1804506 T allele reduced the binding of miR-19a-3p and TGFBR3 3'-UTR.ConclusionsOur findings suggest that the rs1804506 polymorphism in miR-17-92 cluster binding sites contributes to the susceptibility of ESCC, which might provide new clues and scientific evidence for the etiology and biomarkers for the prevention and treatment of ESCC.

Dataset Information

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

Publications

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

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