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Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma. Wójcicka Anna,Czetwertyńska Małgorzata,Świerniak Michał,Długosińska Joanna,Maciąg Monika,Czajka Agnieszka,Dymecka Kinga,Kubiak Anna,Kot Adam,Płoski Rafał,de la Chapelle Albert,Jażdżewski Krystian Genes, chromosomes & cancer The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. 10.1002/gcc.22162
Assessing thyroid cancer risk using polygenic risk scores. Liyanarachchi Sandya,Gudmundsson Julius,Ferkingstad Egil,He Huiling,Jonasson Jon G,Tragante Vinicius,Asselbergs Folkert W,Xu Li,Kiemeney Lambertus A,Netea-Maier Romana T,Mayordomo Jose I,Plantinga Theo S,Hjartarson Hannes,Hrafnkelsson Jon,Sturgis Erich M,Brock Pamela,Nabhan Fadi,Thorleifsson Gudmar,Ringel Matthew D,Stefansson Kari,de la Chapelle Albert Proceedings of the National Academy of Sciences of the United States of America Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points ( ≤ 1.0 × 10). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC. 10.1073/pnas.1919976117
Differentiated thyroid carcinoma: a polygenic disease. Links T P,van Tol K M,Meerman G J,de Vries E G Thyroid : official journal of the American Thyroid Association Differentiated thyroid cancer is a rare disease and until recently was considered to be sporadic. However, increasing evidence has been found for a genetic basis of this disease. In approximately 5% of patients the differentiated thyroid cancer is dominantly inherited. Several families with different syndromes, of which differentiated thyroid cancer is a feature, have already been described. However, until now, single genes explain only a minority of cases. We hypothesize that differentiated thyroid cancer is a polygenic disease. Data from epidemiologic studies, about occult and multifocal carcinomas and the different response to specific risk factors contribute to this hypothesis. 10.1089/10507250152740975
Molecular genetics of thyroid cancer. Rebaї Maha,Rebaї Ahmed Genetics research The pathogenesis of the development and progression of thyroid cancer (TC) is far from being clear at present. Accumulated evidence suggests that it is a complex polygenic disorder for which genetic factors play an important role in disease aetiology. Here we review the literature to report the genetic variations and alterations that have been described in the aetiology of TC. The functional effects of some mutations and single nucleotide polymorphisms on TC are validated, establishing the role of sequence variations in this cancer. However, large prospective studies are still required to evaluate the diagnostic and prognostic value of these genetic determinants in clinical practice. 10.1017/S0016672316000057
GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Zhou Wei,Brumpton Ben,Kabil Omer,Gudmundsson Julius,Thorleifsson Gudmar,Weinstock Josh,Zawistowski Matthew,Nielsen Jonas B,Chaker Layal,Medici Marco,Teumer Alexander,Naitza Silvia,Sanna Serena,Schultheiss Ulla T,Cappola Anne,Karjalainen Juha,Kurki Mitja,Oneka Morgan,Taylor Peter,Fritsche Lars G,Graham Sarah E,Wolford Brooke N,Overton William,Rasheed Humaira,Haug Eirin B,Gabrielsen Maiken E,Skogholt Anne Heidi,Surakka Ida,Davey Smith George,Pandit Anita,Roychowdhury Tanmoy,Hornsby Whitney E,Jonasson Jon G,Senter Leigha,Liyanarachchi Sandya,Ringel Matthew D,Xu Li,Kiemeney Lambertus A,He Huiling,Netea-Maier Romana T,Mayordomo Jose I,Plantinga Theo S,Hrafnkelsson Jon,Hjartarson Hannes,Sturgis Erich M,Palotie Aarno,Daly Mark,Citterio Cintia E,Arvan Peter,Brummett Chad M,Boehnke Michael,de la Chapelle Albert,Stefansson Kari,Hveem Kristian,Willer Cristen J,Åsvold Bjørn Olav Nature communications Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors. 10.1038/s41467-020-17718-z