title: A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma.
abstract: KCNQ1 overlapping transcript 1 (KCNQ1OT1), a long noncoding RNA responsible for silencing a cluster of genes in cis, has been shown to be involved in multiple cancers. However, much remains unclear of how KCNQ1OT1 contributes to carcinogenesis. By thoroughly analyzing 510 hepatocellular carcinoma (HCC) cases and 1014 healthy controls in a Chinese population, we identified a novel short tandem repeat (STR) polymorphism (rs35622507) within the KCNQ1OT1 coding region and evaluated its association with HCC susceptibility. Logistic regression analysis showed that compared with individuals carrying the homozygote 10-10 genotype, those heterozygote subjects who carry only one allele 10 had a significantly decreased risk of HCC (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]=0.53-0.86, p=0.0009), with the risk decreased even further in those without allele 10 (adjusted OR=0.38, 95% CI=0.21-0.69, p=0.0005). Furthermore, genotype-phenotype correlation studies using four hepatoma cell lines support a significant association between STR genotypes and the expression of KCNQ1OT1. Cell lines without allele 10 conferred a 20.9-33.3-fold higher expression of KCNQ1OT1. Meanwhile, KCNQ1OT1 expression was reversely correlated with the expression of the cyclin-dependent kinase inhibitor 1C (CDKN1C), a tumor suppressor gene located within the CDKN1C/KCNQ1OT1 imprinted region, in three hepatoma cell lines. Finally, in silico prediction suggested that different alleles could alter the local structure of KCNQ1OT1. Taken together, our findings suggest that the STR polymorphism within KCNQ1OT1 contributes to hepatocarcinogenesis, possibly by affecting KCNQ1OT1 and CDKN1C expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our hypothesis and understand the roles of KCNQ1OT1 polymorphisms in predisposition for HCC.
authors.affiliation: 1 Department of Forensic Medicine, Medical College of Soochow University , Suzhou, People's Republic of China .
authors.forename: Jiao
authors.initials: J
authors.lastname: Wan
authors.forename: Moli
authors.initials: M
authors.lastname: Huang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Wang
authors.forename: Xiankun
authors.initials: X
authors.lastname: Zhao
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.forename: Shizhong
authors.initials: S
authors.lastname: Bian
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003198:Computer Simulation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics; D017510:Protein Folding
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; C485621:KCNQ1OT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated