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

Pharmgenomics Pers Med. 2021 May 6;14:533-544. doi: 10.2147/PGPM.S300783. eCollection 2021.

Abstract

Objective: 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: BRCA2; DNA double-strand break repair; hsa-miR-1178-3p; papillary thyroid carcinoma; rs15869 polymorphism.

Grant support

This study was supported by grants from the clinical research project of Climbing Fund from the National Cancer Center (No.NCC201806B-009), Liaoning Provincial Key Research and Development Program (No.2017225056) and Liaoning natural fund guidance plan (No.2019-ZD-0595).