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. © 2014 Wiley Periodicals, Inc.
CITATION STYLE
Wójcicka, A., Czetwertyńska, M., Świerniak, M., Dlugosińska, J., Maciag, M., Czajka, A., … Jazdzewski, K. (2014). Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma. Genes Chromosomes and Cancer, 53(6), 516–523. https://doi.org/10.1002/gcc.22162
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