Abstract
BackgroundExcision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results.Methodology/Principal FindingsTo derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92–1.06, P = 0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93–1.03, P = 0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression.Conclusions/SignificanceThis meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.
Highlights
Exposure to environmental carcinogens can cause different types of DNA damage that subsequently lead to carcinogenesis of different tissues, if left unrepaired
On the basis of eligible 49 case-control studies with a total of 23490 cancer cases and 27168 controls, our meta-analysis comprehensively evaluated the association between the excision repair cross complementing group 5 (ERCC5) Asp1104 His polymorphism and risk of different types of cancers, and we did not find statistical evidence for such an association in the recessive genetic models as shown in the xeroderma pigmentosum (XP) syndrome
DNA repair deregulation is a crucial factor in the multistep process of carcinogenesis, and the ERCC5 gene is a vital component of the DNA repair machinery
Summary
Exposure to environmental carcinogens can cause different types of DNA damage that subsequently lead to carcinogenesis of different tissues, if left unrepaired. More than 150 human DNA repair genes have been identified in five major pathways: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), double-strand break repair (DSBR), and transcription coupled repair (TCR) Of those pathways, NER is the most studied DNA repair mechanism responsible for various types of DNA damage, including thymidine dimers, oxidative DNA damage, bulky adducts cross-links, and alkylating damage [1]. Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. A series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G.C) and cancer susceptibility generated conflicting results
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