title: The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type.
abstract: A genome-wide association study of papillary thyroid carcinoma (PTC) pinpointed two independent SNPs (rs944289 and rs965513) located in regions containing no annotated genes (14q13.3 and 9q22.33, respectively). Here, we describe a unique, long, intergenic, noncoding RNA gene (lincRNA) named Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3) located 3.2 kb downstream of rs944289 at 14q.13.3 and the expression of which is strictly thyroid specific. By quantitative PCR, PTCSC3 expression was strongly down-regulated (P = 2.84 × 10(-14)) in thyroid tumor tissue of 46 PTC patients and the risk allele (T) was associated with the strongest suppression (genotype [TT] (n = 21) vs. [CT] (n = 19), P = 0.004). In adjacent unaffected thyroid tissue, the genotype [TT] was associated with up-regulation of PTCSC3 ([TT] (n = 21) vs. [CT] (n = 19), P = 0.034). The SNP rs944289 was located in a binding site for the CCAAT/enhancer binding proteins (C/EBP) α and β. The risk allele destroyed the binding site in silico. Both C/EBPα and C/EBPβ activated the PTCSC3 promoter in reporter assays (P = 0.0009 and P = 0.0014, respectively) and the risk allele reduced the activation compared with the nonrisk allele (C) (P = 0.026 and P = 0.048, respectively). Restoration of PTCSC3 expression in PTC cell line cells (TPC-1 and BCPAP) inhibited cell growth (P = 0.002 and P = 0.019, respectively) and affected the expression of genes involved in DNA replication, recombination and repair, cellular movement, tumor morphology, and cell death. Our data suggest that SNP rs944289 predisposes to PTC through a previously uncharacterized, long intergenic noncoding RNA gene (PTCSC3) that has the characteristics of a tumor suppressor.
authors.affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Jendrzejewski
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jerneja
authors.initials: J
authors.lastname: Tomsic
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015152:Blotting, Northern; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019556:COS Cells; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D022661:RNA, Untranslated / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D022661:RNA, Untranslated