Effect of Repair Gene Polymorphism on the Risk of Malignant Neoplasm Development after Chronic Radiation Exposure

Abstract

The efficiency of DNA integrity repair processes after radiation exposure may depend on hereditary variations of repair genes caused by single nucleotide polymorphisms. Disturbances or even failure of repair processes trigger a chain of reactions leading to genome instability and oncogenic transformation of the cell. Purpose. To investigate the association of single nucleotide polymorphism in genes of nucleotide excision repair (ERCC2 rs13181, XPC rs2228001), AP site repair (APEX rs1130409), homologous recombination (XRCC3 rs861539), single-strand DNA break repair (XRCC1 rs25487), and double-strand DNA break repair (PARP rs1136410, XRCC4 rs2075685) with the risk of development of malignant neoplasms of various localizations in chronically exposed persons. Materials and methods. The study was perfomred in 861 individuals who were chronically exposed to low-dose low-rate radiation, 274 of which had malignant neoplasms (MN) of various localizations and 587 made up the comparison group (exposed persons without MN). The mean cumulative dose to red bone marrow (RBM) in the group of people with MN was 561.65 ± 25.31 mGy, while in the comparison group it was 543.14 ± 36.06 mGy. Genotyping of polymorphic loci rs13181, rs2228001, rs1130409, rs861539, rs25487, rs1136410, and rs2075685 was performed by real-time PCR. The association of polymorphic loci with the risk of MN development was determined by the odds ratio (OR) and 95% confidence interval (95% CI). A multifactor dimensionality reduction method was used to assess intergenic interactions. Results. Single-stranded DNA break repair gene (XRCC1) rs25487 polymorphism in accordance with the dominant model is associated with an increased risk of MN development in the combined group of the examined persons (OR = 1.79 (1.12‒2.87), p = 0.01) and in the Slavs group (OR = 2.26; 95% CI 1.06-4.81; p = 0.03). The rs861539 polymorphism of the gene involved in homologous recombination (XRCC3) in accordance with the recessive model is associated with a reduced risk of MN development both in the combined group of exposed persons (OR = 0.25 (0.15‒0.41); p < 0.00001) and separately in the group of the Slavs (OR = 0.28 (0.13‒0.60); p < 0.0001) and in the group of the Turkic people (OR = 0.22 (0.11‒0.44); p < 0.0001). The model of interfactorial interactions allowed us to establish a protective effect with respect to the risk of MN development in the carriers of polymorphic loci rs861539 of the XRCC3 gene and rs1130409 of the APEX1 gene (p < 0.001).