title: Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.
abstract: 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.
authors.affiliation: Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw 02-091, Poland; Centre of New Technologies, CENT, University of Warsaw, Warsaw 02-089, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wójcicka
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Czetwertyńska
authors.forename: Michał
authors.initials: M
authors.lastname: Świerniak
authors.forename: Joanna
authors.initials: J
authors.lastname: Długosińska
authors.forename: Monika
authors.initials: M
authors.lastname: Maciąg
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Czajka
authors.forename: Kinga
authors.initials: K
authors.lastname: Dymecka
authors.forename: Anna
authors.initials: A
authors.lastname: Kubiak
authors.forename: Adam
authors.initials: A
authors.lastname: Kot
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Krystian
authors.initials: K
authors.lastname: Jażdżewski
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002291:Carcinoma, Papillary; D064447:Checkpoint Kinase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D044465:White People
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human