Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2014) 35 P1129 | DOI: 10.1530/endoabs.35.P1129

ECE2014 Poster Presentations Thyroid Cancer (70 abstracts)

The role of ATM–CHEK2–BRCA1 axis in determination of genetic predisposition and clinical presentation of papillary thyroid carcinoma

Anna Wojcicka 1, , Malgorzata Czetwertynska 1, , Michal Swierniak 1, , Joanna Dlugosinska 1, , Monika Maciag 1 , Agnieszka Czajka 1 , Kinga Dymecka 1 , Adam Kot 1, , Rafal Ploski 5 & Krystian Jazdzewski 1,


1Genomic Medicine, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; 2Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland; 3Department of Endocrine Oncology and Nuclear Medicine, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; 4Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; 5Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.

Background: Risk of developing papillary thyroid carcinoma (PTC), the most frequent thyroid malignancy, is elevated up to 8.6-fold in the first-degree relatives of PTC patients, what could be explained by 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. Among the DNA repair proteins, the ATM–CHEK2–BRCA1 axis seems to be of particular interest. In response to double-strand DNA breaks, ATM is recruited to DNA damage sites, phosphorylating BRCA1 and CHEK2 and initiating a signalling cascade of DNA damage response and cell-cycle control proteins.

Aim of the study: The aim of this study was to identify low-penetrance susceptibility alleles for PTC by genotyping deleterious SNPs in genes involved in DNA damage-response and cell-cycle pathways.

Methods and results: Sequenom iPLEX technology was employed to genotype polymorphisms: rs1801516 in ataxia telangiectasia mutated (ATM), rs17879961 in CHEK2 checkpoint yeast homolog (CHEK2), and rs16941 in breast cancer 1 gene (BRCA1) in 1781 PTC patients and 2081 healthy controls. We identified BRCA1 rs16941 (odds ratio (OR)=1.16, P=0.005) and CHEK2 rs17879961 (OR=2.2, P=2.37×10−10) as the risk alleles for PTC. ATM rs1801516 variant modifies the risk associated with BRCA1 variant by 0.78 (P=0.02). Both 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).

Conclusion: This is the first study showing the complex association between genetic variants of ATM–CHEK2–BRCA1 axis and the predisposition to PTC. The study supports previous findings on the importance of age and gender on the clinical outcome of the disease and showed that this effect is significantly altered by the minor alleles of the analysed genes, emphasizing their importance in the pathogenesis of PTC.

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