Abstract
BackgroundHundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition–unwinding–incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk.ResultsIn screening stage, single-locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 × 10−4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene–gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression.MethodsThis study designed as “screening-verification” experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene.ConclusionsXPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk.
Highlights
Hepatocellular cancer (HCC) is the sixth most common type of cancer and the third most frequent cause of cancer death worldwide [1, 2]
Among these 39 single nucleotide polymorphism (SNP), six SNPs in five genes were associated with hepatocellular cancer (HCC) risk in stage 1, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601)
Two positive SNPs were identified in ERCC1, rs2298881 and rs3212961, which were associated with a decreased HCC risk (OR = 0.64 and 0.60, respectively, Table 1) when the heterozygote was compared with the wild-type
Summary
Hepatocellular cancer (HCC) is the sixth most common type of cancer and the third most frequent cause of cancer death worldwide [1, 2]. Several single nucleotide polymorphisms (SNPs) in some genes involved in oxidative stress, metabolism and inflammation pathways, have been proved to be associated with HCC risk [3]. These SNPs have great significance for the selection of individuals who benefit from specific preventative measures [3]. DNA repair systems include nucleotide excision repair (NER), base excision repair, mismatch repair, and double-strand break repair [4]. Among these repair systems, the NER system is most frequently associated with cancer [5]. Only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk
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