Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

Abstract

XPC, a key protein in the nucleotide excision repair (NER) pathway, recognizes damaged DNA and initiates NER. Genetic variations in the XPC gene might be associated with altered DNA repair capacities (DRC). In this study, we genotyped three XPC polymorphisms, Ala499Val (C→T), PAT (-/+) and Lys939Gln (A→C), and measured the DNA damage/DRC by alkaline comet assay challenged by BPDE and gamma-radiation in 476 healthy subjects. We also evaluated the associations between DNA damage/DRC and genotypes of XPC polymorphisms. Compared with the XPC Lys939Gln homozygous wild type (AA) subjects, subjects with the variant alleles (AC and CC) had significantly higher DNA damages induced by BPDE (Median and 95% confidence interval [CI]: 3.16 (3.01-3.44) vs. 2.88 (2.51-3.05), P=0.01), and gamma-radiation (4.18(3.94-4.44) vs. 3.71 (3.49-4.04), P=0.01). However, subjects with the variant alleles (CT and TT) of Ala499Val exhibited a 8.6 % and 13.1% decrease in DNA damages induced by BPDE (P=0.05) and gamma-radiation (P=0.001), respectively. Significant correlations were found between genotypes and induced DNA damages in XPC Lys939Gln (For BPDE: R=0.12, P=0.01; for gamma-radiation: R=0.094, P=0.046) and Ala499Val (For BPDE: R=-0.11, P=0.03; for gamma-radiation: R=-0.16, P=0.0009). The haplotypes "T-A" (in the order of Ala499Val-PAT-Lys939Gln) was associated with the lowest DNA damages. Our results suggested that the DRC of host cells might be modulated by specific XPC polymorphisms.

Xeroderma pigmentosum complementation group C single‐nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression‐free survival in advanced ovarian cancer

“…The 3 most common polymorphisms reported in the literature and associated with cancer development are the alanine-to-valine substitution at codon 499 (Ala499Val; rs2228000), PAT (À/þ), and the lysine-toglutamine substitution at codon 939 (Lys939Gln; rs2228001). 21 We tested 7 XPC SNPs in total, which included the 3 most common XPC SNPs. Three intronic XPC SNPs from our panel (XPC-PAT, rs3731108, and rs1124303) were associated with prolonged PFS, possibly suggesting improved platinum sensitivity.…”

“…The deletion of exon 12 results in the loss of function of XPC, leading to an increase in cancer development. [21][22][23][24] Our study indicated that patients with the XPC-PAT (þ/þ) genotype had decreased platinum sensitivity and worse PFS. This suggests a possible mechanism of how SNPs in intronic sequences can have effects on coding regions, ultimately leading to changes in protein and gene expression.…”

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

“…Unfortunately, functional studies for this polymorphism have also yielded inconsistent results. 26,27 Additional studies are required to evaluate the role of XPC variations in cisplatin response and ototoxicity.…”

XPC genetic polymorphisms correlate with the response to imatinib treatment in patients with chronic phase chronic myeloid leukemia

“…These two polymorphisms involve changes in protein sequence [22,24] and have been associated with the risk of developing several cancers [25][26][27]. Moreover, experimental data [28,29] suggest that both the TA and the CC haplotypes result in protein variants that are less active in DNA repair than the CA wild-type. We found that the CA wild-type haplotype was associated with a favorable response to imatinib, as patients who carried one or two copies of such haplotype had a fourfold lower risk of achieving suboptimal response or failure to imatinib than the remainders.…”