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.germline variant | transcriptional regulation | tissue specific expression

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

“…Recent studies have indicated that lncRNAs are transcribed from cancer risk loci and that these transcripts can play important roles in tumorigenesis. [30][31][32] Here, we used RNA-seq to identify two estrogenregulated lncRNAs (CUPID1 and CUPID2) that might contribute to the risk of developing breast cancer by modulating pathway choice of DSB repair.…”

“…Ingenuity Pathway Analysis (IPA) on the differentially expressed genes was conducted as described previously. 14 Expression of CUPID1 and CUPID2 in TCGA Cohort RNA-seq data from The Cancer Genome Atlas (TCGA) breast invasive carcinoma cohort (1,226 samples) were obtained from the UCSC Cancer Genomics Hub (September 30,2015). The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national), and proper informed consent was obtained.…”

X-Ray Repair Cross-Complementing Group 1(XRCC1) Genetic Polymorphisms and Thyroid Carcinoma Risk: a Meta-Analysis

“…XRCC1 plays an important role in the DNA repair pathway because it could specifically interact with nicked and gapped DNA, rapidly and transiently responds to DNA damage in cells, thus may serve as a strand-break sensor (Mani et al, 2004). In addition, XRCC1 could interact with many proteins known to be involved in BER andSSBR, so it has been proposed that XRCC1 may function as a scaffold protein able to coordinate and facilitate the steps of various DNA repair pathways (Mani et al, 2007). It is widely accepted that alterations in XRCC1 may play important roles in the process associated with the etiology of cancers because of the alteration of base excision repair functions (Monaco et al, 2007).…”

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…71 The G allele of rs6983267, in addition to being related to a significantly increased risk of CRC, 72 results in more CCAT2 transcripts than the T allele, which further affects the regulation of MYC by CCAT2; thus different rs6983267 alleles can affect CCAT2 expression and function. 58 Studies examining other cancer types have shown that SNPs in the key regulatory regions of an lncRNA can alter its structural motifs 73 and may consequently affect its expression and function in malignancies, 74 additionally contributing to cancer risk. 75,76 SNPs in the cancer-associated lncRNAs could potentially have pivotal roles in colorectal tumorigenesis and progression.…”