Abstract
BackgroundExcision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.Methodology/Principal FindingsIn this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50–0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58–1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40–0.92 for rs2276466; OR = 0.69, 95% CI: 0.48–0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.ConclusionsThese results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.
Highlights
DNA repair plays a critical role in protecting the genome from insults caused by carcinogenic agents, such as carcinogens presented in tobacco smoke, ultraviolet light and ionizing radiation
We previously reported that the relative protein expression level of ERCC4 was significantly lower in the SCCHN cases than in the controls, and the risk of SCCHN associated with low expression of ERCC4 was higher by 11-fold [25]
We found that smoking and alcohol drinking was associated with a significant increased risk of SCCHN, respectively (OR = 2.18; 95% confidence interval (CI): 1.81–2.64 for smoking; odds ratio (OR) = 1.71; 95% CI: 1.41–2.18 for drinking)
Summary
DNA repair plays a critical role in protecting the genome from insults caused by carcinogenic agents, such as carcinogens presented in tobacco smoke, ultraviolet light and ionizing radiation. In addition to NER, the ERCC4/ERCC1 complex is suggested to play a role in removal of DNA interstrand cross-links (ICL), DNA double-strand breaks (DSB), and immunoglobulin class switch recombination (CSR) [11,12,13,14] Germ-line mutations in ERCC4, among other XP genes in the NER pathway, are associated with some rare inherited human syndromes, such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD) [15]. These syndromes fit a recessive genetic model, in which heterozygotes are unaffected, but mutant homozygotes manifest the disease [16]. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility
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