Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

Son, Ho Young; Hwangbo, Yul; Yoo, Seong Keun; Im, Sangjun; Yang, San‐Duk; Kwak, Soo Jung; Park, Min Seon; Kwak, Soo Heon; Cho, Sun Wook; Ryu, Junsun; Kim, Jeongseon; Jung, Yuh Seog; Kim, Tae Hyun; Kim, Su Jin; Lee, Kyu Eun; Park, Do Joon; Cho, Nam Han; Sung, Joohon; Seo, Jeong Sun; Lee, Eun Kyung; Park, Young Joo; Kim, Jong‐Il

doi:10.1038/ncomms15966

Cited by 68 publications

(83 citation statements)

References 62 publications

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“…Much effort has been made to identify such susceptibility variants. The most robust evidence is for markers at 9q22.33 (FOXE1), 14q13.3 (NKX2-1), 2q35 (DIRC3) and 8p12 (NRG1), as variants in these regions have been repeatedly associated with DTC through several genome-wide association studies (GWASs), confirmed in follow-up studies and independently replicated across different populations (6)(7)(8)(9)(10)(11)(12). Additional markers have recently been suggested (8,(10)(11)(12)(13) but still require confirbut still require confirmation and replication.…”

Section: Introductionmentioning

confidence: 75%

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Santos

Silva

et al. 2018

Oncol Lett

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Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes ( rs1799977, rs26279, rs5745325, rs5742933, rs175080 and rs1042821) were genotyped through TaqMan assays and genotype-associated risk estimates were calculated. An increased risk was observed in rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when was analysed in combination with other MMR SNPs such as rs26279. Interestingly, two other SNP combinations, both containing the heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

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Section: Introductionmentioning

confidence: 75%

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Santos

Silva

et al. 2018

Oncol Lett

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“…TTF1 levels from 3 independent experiments were quantified with ImageJ software. *P , 0.05, **P , 0.01 compared to 0 h. In addition to normal HTori3 cells, TTF1 expression has been found in a variety of thyroid tumor cells, such as follicular adenomas, follicular carcinomas, and papillary carcinomas (10)(11)(12). We observed that TTF1 expression levels were divergent in these cells.…”

Section: Discussionmentioning

confidence: 58%

“…TTF1 is important for regulation of TG, thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) expression (1,8,9). Among thyroid tumors, TTF1 is expressed in all tumors of follicular derivation, such as follicular adenoma and follicular and papillary carcinoma (10)(11)(12). The C-cell-derived medullary carcinomas are positive for TTF1 immunoreactivity (13,14).…”

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confidence: 99%

Two distinct E3 ligases, SCF^FBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively

et al. 2019

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Thyroid transcription factor 1 (TTF1) regulates the tissue‐specific expression of genes. However, the molecular regulation of TTF1 in thyroid normal and carcinoma cells has not been revealed. Here we identify 2 distinct ubiquitin E3 ligases that are responsible for TTF1 degradation in normal thyroid cells and carcinoma cells, respectively. Phorbol myristate acetate induced TTF1 protein degradation in the ubiquitin‐proteasome system in both HTori3 thyroid follicular epithelial cells and follicular thyroid carcinoma 133 (FTC133) cells. Lysine 151 residue was identified as a ubiquitin acceptor site within TTF1 in both cell types. Overexpression of E3 ubiquitin protein ligase 1 containing HECT, C2, and WW domain (HECW1) induced TTF1 degradation and ubiquitination in Htori3 cells but not in FTC133 cells. Overexpression of ubiquitin E3 ligase subunit FBXL19 increased TTF1 ubiquitination and degradation in FTC133 cells, but it had no effect on TTF1 levels in Htori3 cells. Overexpression of TTF1 increased thyroglobulin and sodium/iodide symporter mRNA levels, cell migration, and proliferation in HTori3 cells, whereas the effects were reversed by the overexpression of HECW1. This study reveals an undiscovered molecular mechanism by which TTF1 ubiquitination and degradation is regulated by different E3 ligases in thyroid normal and tumor cells.—Liu, J., Dong, S., Wang, H., Li, L., Ye, Q., Li, Y., Miao, J., Jhiang, S., Zhao, J., Zhao, Y. Two distinct E3 ligases, SCFFBXL19 and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively. FASEB J. 33, 10538–10550 (2019). http://www.fasebj.org

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“…For DTC, 31 associations have been reported (Tab. I) [20][21][22][23][24][25][26][27]. SNPs uncovered by GWAS are located on 12 chromosomes in 17 different loci.…”

Section: Reviewmentioning

confidence: 99%

Clinical implications of GWAS variants associated with differentiated thyroid cancer

Jendrzejewski

Sworczak

Comiskey

et al. 2019

Endokrynologia Polska

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The genetic risk of differentiated thyroid cancer (DTC) probably consists of multiple low-penetrance, single-nucleotide polymorphisms (SNP). Such markers are difficult to uncover by linkage analysis but can be revealed by association studies. Genome-wide association studies (GWASs) have uncovered 31 SNPs associated with DTC. These markers carry a low to moderate risk for DTC, but their cumulative effect increases with each successive risk allele. These data support the important contribution of low penetrance variants in the pathogenesis of DTC. Contrary to somatic mutations such as BRAFV600E, germline variants can be ascertained prior to surgical treatment. Therefore, we hypothesise that GWAS SNPs might impact the clinical course of DTC and we can benefit from this knowledge in choosing a treatment strategy. Several associations between clinical factors and GWAS markers have been reported so far. The most important are associations between rs966423 and mortality (HR = 1.60, p = 0.038), extrathyroidal extension (ETE) (OR = 1.57, p = 0.019); rs965513 and tumour diameter (slope of regression 0.14, p = 0.025), lymph node metastasis (OR = 1.59, p = 0.030) and ETE (OR = 1.29, p = 0.045); rs944289 and distant metastasis (OR = 0.58, p = 0.042); and rs116909374 and lymph node metastasis (OR = 0.61, p = 0.016). These findings show that GWAS SNPs are not only the ignition factors (together with environmental factors) for malignant transformation of thyrocytes but might also impact the clinical course of DTC. Surprisingly, it is not always the risk allele for DTC that is associated with worse clinical outcome. The second interesting observation is that GWAS SNPs show different associations with DTC clinical features depending on their histological subtypes. These point to the complexity of DTC with putatively different roles of genes at different stages of DTC development.

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Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

Cited by 68 publications

References 62 publications

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Two distinct E3 ligases, SCF^FBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively

Clinical implications of GWAS variants associated with differentiated thyroid cancer

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Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

Cited by 68 publications

References 62 publications

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

Two distinct E3 ligases, SCFFBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively

Clinical implications of GWAS variants associated with differentiated thyroid cancer

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Two distinct E3 ligases, SCF^FBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively