BRCA2 3ʹ-UTR Polymorphism rs15869 Alters Susceptibility to Papillary Thyroid Carcinoma via Binding hsa-mir-1178-3p

Nan Guo,1 Peng Qu,2 Hao Li,2 Liuli Liu,2 Hao Jin,3 Renqi Liu,3 Zhen Zhang,3 Xuan Zhang,2 Yingchun Li,4 Xiaobo Lu,2 Yuejiao Zhao1 1Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of China; 2Department of Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China; 3Jin Zhou Center for Disease Control and Prevention, Jinzhou, People’s Republic of China; 4Department of Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of ChinaCorrespondence: Yuejiao ZhaoDepartment of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, People’s Republic of ChinaTel +86 24 31916833Email yuejiaozhao@126.comXiaobo LuDepartment of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People’s Republic of ChinaTel +86 24 31939077Email xblu@cmu.edu.cnObjective: To investigate the associations of polymorphisms in the following DNA double-strand break repair (DSBR) genes with papillary thyroid carcinoma (PTC) risk (including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440).Materials and Methods: A matched case–control study was implemented to examine associations between PTC risk and the above polymorphisms. Subsequently, we evaluated the effects of the potential PTC susceptibility-related variant rs15869 on BRCA2 mRNA secondary structure and BRCA2 expression through bioinformatics analysis and experiment validation. Additionally, luciferase assay was used to identify whether rs15869 polymorphism can substantially affect the binding of hsa-miR-1178-3p to BRCA2 mRNA. Finally, Pearson correlation analysis was performed to determine the correlation between the expression of hsa-miR-1178-3p and BRCA2 mRNA and protein in thyroid tissues harboring rs15869 different genotypes.Results: BRCA2 rs15869 CC genotype was associated with a higher risk of PTC than its AA genotype. Subsequently, stratified analyses came to the same conclusion in the female or age< 50 population. Furthermore, we confirmed that the A-to-C substitution of rs15869 changed BRCA2 mRNA secondary structure and contributed to a decreased BRCA2 expression. Mechanistically, a significantly decreased luciferase activity verified a greater binding between hsa-miR-1178-3p and rs15869 C allele, but not the A allele, which was evidenced by the significant negative correlation between hsa-miR-1178-3p with BRCA2 mRNA and protein levels in thyroid tissues with AC and CC genotype but not AA genotype at rs15869.Conclusion: BRCA2 rs15869 is characterized as a potential biomarker associated with PTC risk, highlighting the contribution of the hsa-miR-1178-3p via functional exploration.Keywords: papillary thyroid carcinoma, DNA double-strand break repair, BRCA2, rs15869 polymorphism, hsa-miR-1178-3p