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

Liyanarachchi, Sandya; Wójcicka, Anna; Li, Wei; Czetwertyńska, Małgorzata; Stachlewska, Elżbieta; Nagy, Rebecca; Hoag, Kevin W.; Wen, Bernard; Płoski, Rafał; Ringel, Matthew D.; Kozłowicz-Gudzińska, Izabella; Gierlikowski, Wojciech; Jażdżewski, Krystian; He, Hao; Chapelle, Albert de la

doi:10.1089/thy.2013.0102

Cited by 66 publications

(72 citation statements)

References 38 publications

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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).…”

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confidence: 71%

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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confidence: 71%

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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“…Several germline changes have been reported to predispose to DTC, including variants in microRNA-146a, ATM-CHEK2-BRCA1 pathway, TERT gene, and 5 SNPs pinpointed by GWAS study (2)(3)(4)(5)(12)(13)(14)(15). So far, no study revealed the influence of germline (inherited) variants on the overall mortality of patients with thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we revealed a cumulative, additive effect of rs116909374, rs965513, rs944289, rs966423, and rs2439302 on the thyroid cancer risk (4). Because the influence of polymorphic variants on the overall survival has never been established, we analyzed the association of these SNPs with the mortality of patients with thyroid cancer.…”

Section: Introductionmentioning

confidence: 98%

“…In a search of pretreatment clinical markers determining the poor prognosis of patients with thyroid cancer, we tested the impact of five inherited polymorphisms on overall survival. All five markers (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been previously shown by genome-wide association studies (GWAS) to increase the risk of differentiated thyroid cancer; however their impact on the clinical outcome has not been established (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…Several large case-control studies, including hypothesis-free GWAS, have convincingly demonstrated genetic factors predisposing to DTCs (2)(3)(4)(5)(6). Still, there are no data showing the effect of SNPs on the survival rates of patients with thyroid cancer.…”

Section: Introductionmentioning

confidence: 99%

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Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

Świerniak

Wójcicka

Czetwertyńska

et al. 2016

Clinical Cancer Research

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Purpose: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC.Experimental Design: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013.Results: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P ¼ 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P ¼ 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P ¼ 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P ¼ 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P ¼ 0.013).Conclusions: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.

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Significant SNPs have limited prediction ability for thyroid cancer

Guo

Wang

et al. 2014

Cancer Medicine

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Recently, five thyroid cancer significantly associated genetic variants (rs965513, rs944289, rs116909374, rs966423, and rs2439302) have been discovered and validated in two independent GWAS and numerous case–control studies, which were conducted in different populations. We genotyped the above five single nucleotide polymorphisms (SNPs) in Han Chinese populations and performed thyroid cancer-risk predictions with nine machine learning methods. We found that four SNPs were significantly associated with thyroid cancer in Han Chinese population, while no polymorphism was observed for rs116909374. Small familial relative risks (1.02–1.05) and limited power to predict thyroid cancer (AUCs: 0.54–0.60) indicate limited clinical potential. Four significant SNPs have limited prediction ability for thyroid cancer.

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

Cited by 66 publications

References 38 publications

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

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

Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

Significant SNPs have limited prediction ability for thyroid cancer

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