Epistatic SNP interaction of ERCC6 with ERCC8 and their joint protein expression contribute to gastric cancer/atrophic gastritis risk.

Jing-Jing Jing,Nan-Nan Dong,Li-Ping Sun,Yuan Yuan,Yue-Hua Gong,Qian Xu,You-Zhu Lu,Jing-Wei Liu

doi:10.18632/oncotarget.17814

Abstract

Excision repair cross-complementing group 6 and 8 (ERCC6 and ERCC8) are two indispensable genes for the initiation of transcription-coupled nucleotide excision repair pathway. This study aimed to evaluate the interactions between single nucleotide polymorphisms of ERCC6 (rs1917799) and ERCC8 (rs158572 and rs158916) in gastric cancer and its precancerous diseases. Besides, protein level analysis were performed to compare ERCC6 and ERCC8 expression in different stages of gastric diseases, and to correlate SNPs jointly with gene expression. Sequenom MassARRAY platform method was used to detect polymorphisms of ERCC6 and ERCC8 in 1916 subjects. In situ ERCC6 and ERCC8 protein expression were detected by immunohistochemistry in 109 chronic superficial gastritis, 109 chronic atrophic gastritis and 109 gastric cancer cases. Our results demonstrated pairwise epistatic interactions between ERCC6 and ERCC8 SNPs that ERCC6 rs1917799-ERCC8 rs158572 combination was associated with decreased risk of chronic atrophic gastritis and increased risk of gastric cancer. ERCC6 rs1917799 also showed a significant interaction with ERCC8 rs158916 to reduce gastric cancer risk. The expressions of ERCC6, ERCC8 and ERCC6-ERCC8 combination have similarities that higher positivity was observed in chronic superficial gastritis compared with chronic atrophic gastritis and gastric cancer. As for the effects of ERCC6 and ERCC8 SNPs on the protein expression, single SNP had no correlation with corresponding gene expression, whereas the ERCC6 rs1917799–ERCC8 rs158572 pair had significant influence on ERCC6 and ERCC6-ERCC8 expression. In conclusion, ERCC6 rs1917799, ERCC8 rs158572 and rs158916 demonstrated pairwise epistatic interactions to associate with chronic atrophic gastritis and gastric cancer risk. The ERCC6 rs1917799–ERCC8 rs158572 pair significantly influence ERCC6 and ERCC6-ERCC8 expression.

Highlights

Nucleotide excision repair (NER) is a critical and versatile system that monitors and repairs a broad spectrum of DNA damage
We firstly focused on the pairwise interaction effects for Single nucleotide polymorphism (SNP) of Excision repair cross-complementing group 6 (ERCC6) and Excision repair cross-complementing group 8 (ERCC8)
The results indicated that ERCC6 rs1917799 and ERCC8 rs158572 polymorphisms had interaction effects for chronic atrophic gastritis (CAG) and gastric cancer (GC) (Pinteraction=0.013 and 0.021, separately)

Summary

Introduction

Nucleotide excision repair (NER) is a critical and versatile system that monitors and repairs a broad spectrum of DNA damage. NER is composed of global genome nucleotide excision repair (GGR) and transcription-coupled nucleotide excision repair (TCR) [1]. TCR repairs RNA polymerase II (RNAPII) blocking DNA lesions and ensures the transcribed strand of the active gene to be repaired preferentially than the other sites of the genome [2]. ERCC6 (Excision repair cross-complementing group, alternatively known as CSB) and ERCC8 (Excision repair cross-complementing group, alternatively known as CSA) gene, are two indispensable core genes for the initiation of TCR pathway [3]. They were first described in the Cockayne syndrome (CS), a human autosomal recessive disease. ERCC6 and ERCC8 proteins, with direct interaction, jointly participate www.impactjournals.com/oncotarget in DNA repair, transcriptional regulation, maintenance of the chromosome stability and chromatin remodeling [4,5,6]

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