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.

SUBMITTER: Wojcicka A 

PROVIDER: S-EPMC4058861 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature