polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-05, Vol.109 (22), p.8646-8651
• Main Authors: Jendrzejewski, Jaroslaw, He, Huiling, Radomska, Hanna S, Li, Wei, Tomsic, Jerneja, Liyanarachchi, Sandya, Davuluri, Ramana V, Nagy, Rebecca, de la Chapelle, Albert
• Format: Article
• Language: English
• Subjects: Alleles; Animals; binding proteins; Binding sites; Binding Sites - genetics; Biological Sciences; Blotting, Northern; carcinoma; Carcinoma, Papillary - genetics; Carcinoma, Papillary - pathology; CCAAT-Enhancer-Binding Protein-beta - metabolism; cell death; cell growth; Cell Line, Tumor; Cell lines; cell movement; Cell Proliferation; Cercopithecus aethiops; Chromosomes, Human, Pair 14 - genetics; Complementary DNA; COS Cells; DNA replication; Exons; Gene expression; Gene Expression Profiling; gene expression regulation; Gene Expression Regulation, Neoplastic; Genes; Genes, Tumor Suppressor; Genetic Predisposition to Disease - genetics; Genomes; Genotype; HEK293 Cells; Humans; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Papillary carcinoma; patients; polymerase chain reaction; Polymorphism; Polymorphism, Single Nucleotide; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; risk; RNA; RNA, Untranslated - genetics; single nucleotide polymorphism; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; tumor suppressor genes; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1205654109

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 x 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.