Discovery of common variants associated with low TSH levels and thyroid cancer risk

Guðmundsson, Jūlı́us; Sulem, Patrick; Guðbjartsson, Daníel F.; Jonasson, Jón G.; Másson, Gísli; He, Hao; Jónasdóttir, Áslaug; Sigurðsson, Ásgeir; Stacey, Simon; Johannsdottir, Hrefna; Helgadottir, Hafdís T.; Li, Wei; Nagy, Rebecca; Ringel, Matthew D.; Kloos, Richard T.; Visser, Marieke C.; Plantinga, Theo S.; Heijer, Martin den; Aguillo, Esperanza; Panadero, Angeles; Prats, E.; García‐Castaño, Almudena; Juan, Ana De; Rivera, Fernando; Walters, G. Bragi; Bjarnason, Hjördis; Tryggvadóttír, Laufey; Eyjolfsson, Gudmundur I.; Björnsdóttir, Unnur Steina; Hólm, Hilma; Ólafsson, Ísleifur; Kristjánsson, Kristleifur; Kristvinsson, Höskuldur; Magnússon, Ólafur Þ.; Þorleifsson, Guðmar; Gulcher, Jeffrey R.; Kong, Augustine; Kiemeney, Lambertus A.; Jónsson, Þorvaldur; Hjartarson, Hannes; Mayordomo, J. I.; Netea‐Maier, Romana T.; Chapelle, Albert de la; Hrafnkelsson, Jón; Þorsteinsdóttir, Unnur; Rafnar, Thorunn; Stefánsson, Kāri

doi:10.1038/ng.1046

Cited by 220 publications

(292 citation statements)

References 30 publications

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“…So far, exposure to ionizing radiation is the only well established risk factor for thyroid cancer, especially when it occurs in early stages of life (Papadopoulou et al, 2009). However, there are evidences that many gene polymorphisms including DNA repair genes influence on thyroid cancer susceptibility (Gudmundsson et al, 2012(Gudmundsson et al, ,2001Marsin et al, 2003). There have been more than 300 validated SNPs (single nucleotide polymorphism) in the XRCC1 gene, however, only three SNPs have been extensively studied including Arg194Trp, Arg280His and Arg399Gln.…”

Section: Introductionmentioning

confidence: 99%

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

Qian¹,

Liu²,

Xu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Section: Introductionmentioning

confidence: 99%

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

Qian¹,

Liu²,

Xu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Such genes are not amenable to detection by linkage analysis but can be found by association analysis in large datasets (10). Until now, three genome-wide association studies (GWAS) have addressed the predisposition to PTC (11)(12)(13). Gudmundsson et al (11) studied Icelandic PTC patients and controls, followed by validation in Spanish and US cases and controls.…”

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confidence: 99%

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.

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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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“…We studied the predictive value of the five markers detected in two recently published GWASs (22,23). We found that the combined use of the genotypes of these markers shows definite promise as a predictive tool, but that more markers are probably needed before genotyping of markers for PTC can become a routinely applied method in clinical practice.…”

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confidence: 99%

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

Liyanarachchi

Wójcicka

et al. 2013

Thyroid

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Background: Two recent genome-wide association studies (GWASs) identified five single nucleotide polymorphisms (SNPs; rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs. Methods: We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio and 1795 PTC cases and 2090 controls from Poland. Cumulative genetic risk scores were calculated using unweighted and weighted approaches. Results: All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls ( p < 2.2 · 10 Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to three weighted risk score groups, low ( £ 2), medium (2-5), and high (>5). Individuals in the high group were significantly more susceptible to PTC compared with individuals in the low group with an odds ratio of 8.7 [95% CI 5.8, 13.3] in Ohio and 4.24 [95% CI 3.10, 5.84] in Poland. Almost identical results were obtained when follicular variant PTCs and microPTCs were omitted. These five SNPs explained 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort. Conclusion: As the genetic risk score increases, the risk of having PTC increases. However, the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected.

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Discovery of common variants associated with low TSH levels and thyroid cancer risk

Cited by 220 publications

References 30 publications

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

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

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

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

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