title: Genetic variation in an miRNA-1827 binding site in MYCL1 alters susceptibility to small-cell lung cancer.
abstract: Genetic variations in microRNAs (miRNA) that affect control of their target genes may alter individual susceptibilities to cancer. In this study, we took an in silico approach to identify single-nucleotide polymorphisms (SNP) within the 3'-untranslated region (UTR) of miRNA genes deregulated in human small-cell lung cancer (SCLC), and then investigated their associations with SCLC susceptibility in 666 SCLC patients and 758 controls. Odds ratios (OR) were estimated by multivariate logistic regression, and biochemical assays were conducted to investigate SNP functions. We identified 2 SNPs, rs3134615 and rs2291854, which were located in the 3'-UTR of the L-MYC gene MYCL1 and the neuronal development Achaete-Scute Complex homolog ASCL1. Case-control analyses showed that the rs3134615T allele was associated with a significantly increased risk of SCLC, with the OR for carrying the GT or TT genotype being 2.08 (95% confidence interval, 1.39-3.21; P = 0.0004) compared with the GG genotype. In support of the likelihood that these 3'-UTR SNPs may directly affect miRNA-binding sites, reporter gene assays indicated MYCL1 as the target of hsa-miR-1827 and the rs3134615 G>T change resulted in altered regulation of MYCL1 expression. Our findings define a 3'-UTR SNP in the human L-MYC oncogene that may increase susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827.
authors.affiliation: Department of Medical Oncology, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiong
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.forename: Kan
authors.initials: K
authors.lastname: Zhai
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001665:Binding Sites; D018288:Carcinoma, Small Cell / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D012307:Risk Factors; D016037:Single-Blind Method; D012907:Smoking / Q000453:epidemiology
chemical_list: D020413:3' Untranslated Regions; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; C065500:ASCL1 protein, human; C561495:MIRN1827 microRNA, human