Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Mihai, Radu; Moss, Laura; Auton, Adam; Lemon, Catherine; Mehanna, Hisham; Mohan, Hosahalli; Clarke, S. E.M.; Wadsley, Jonathan; Macías, Elena Atienza; Coatesworth, A P; Beasley, Matthew; Roques, Tom; Martin, Craig; Ryan, P. J.; Gerrard, G.; Power, Danielle; Bremmer, Caroline; Tomlinson, Ian; Carvajal‐Carmona, Luis G.

doi:10.1136/jmedgenet-2011-100586

Cited by 98 publications

(115 citation statements)

References 18 publications

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“…Two SNPs that showed highly significant association with PTC were detected (rs965513 and rs944289). The variants were located in 9q22.33 and 14q13.3, respectively, and have been confirmed by other research groups (14,15). As both SNPs were located in gene-poor regions, no immediate candidate genes presented themselves as being affected by or associated with the risk alleles of the SNPs.…”

supporting

confidence: 69%

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

Jendrzejewski

Radomska

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

231

194

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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

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supporting

confidence: 69%

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

Jendrzejewski

Radomska

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

231

194

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“…The same study revealed that tumor DNA of up to 6% of patients undergoes somatic mutations within rs2910164, which additionally confirmed the role of this variant in the pathogenesis of PTC (26). The rs2910164-mediated predisposition was further analyzed in 781 thyroid cancer patients recruited in the United Kingdom (28), and the study revealed no association between the polymorphism and thyroid cancer risk. Similar results were obtained in 753 Chinese patients (29) and in 307 Italian patients (30).…”

Section: Microrna-mediated Thyroid Cancer Riskmentioning

confidence: 77%

MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer

Wójcicka

Kolanowska

Jażdżewski

2016

European Journal of Endocrinology

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MicroRNAs, short non-coding regulators of the gene expression, are subjects of numerous investigations assessing their potential use in the diagnostics and management of human diseases. In this review, we focus on studies that analyze the utility of microRNAs as novel diagnostic and therapeutic tools in follicular cell-derived thyroid carcinomas. This very interesting and promising field brings new insight into future strategies for personalized medicine.

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“…8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5)(6)(7)(8)(9)(10)(11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12)(13)(14)(15).…”

mentioning

confidence: 70%

“…To assess SNPs across the 9q22 locus and to identify functional SNPs, as well as additional associated variants that may contribute to PTC predisposition, we performed targeted next-generation sequencing in a gene-poor region of about 167 kb [genomic coordinates chromosome 9: 100455000-100622000 (GRCh37/hg19)] on DNA from 22 patients with PTC, including 10 [AA], 6 [AG], and 6 [GG] genotypes of the lead SNP rs965513. The region contains both coding genes (XPA and FOXE1) that flank the lead SNP.…”

Section: Resultsmentioning

confidence: 99%

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

Liyanarachchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we finemapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.thyroid cancer | genetic susceptibility | long-range enhancer | functional variants | SNP rs965513 P apillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for >80% of all thyroid malignancy. It is estimated that 62,450 individuals in the United States will be diagnosed with thyroid cancer in 2015 (www.cancer. org/Research/CancerFactsFigures/index). Although PTC is clearly influenced by both genetic and environmental factors, genetic predisposition plays a major role as evidenced by case-control studies (1-3).Genome-wide association studies (GWASs) have linked SNP rs965513 in 9q22 to thyroid cancer, mainly PTC. The odds ratio (OR) for this SNP is as high as ∼1.8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5-11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12-15). SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20). A DNA variant (rs1867277) in the promoter region of FOXE1 was reported as a functional variant involved in transcriptional regulation of FOXE1 (19). However, these studi...

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Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Cited by 98 publications

References 18 publications

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

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

MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

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