Association between LMP 2 and LMP 7 gene polymorphisms and the risk of gastric cancer : A case-control study

The integrality of low molecular weight protein (LMP)2/LMP7 function plays an important role in the processing of GC cell antigens. The purpose of the present hospital-based case-control study was to estimate the effect of polymorphisms in the LMP2 and LMP7 genes on the risk of GC. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to distinguish the Arg to His substitution at codon 60 of LMP2 (LMP2-60) and the Gln to Lys substitution at codon 145 of LMP7 (LMP7-145) in 502 gastric cancer patients and 502 age and gender-matched cancer-free control individuals. The Lys allele of the LMP7-145 variant was more frequent in GC patients compared with control individuals [P=0.004; adjusted odds ratio (OR), 1.39; 95% confidence interval (CI), 1.11‐1.74]. The Gln/Lys and Lys/Lys genotypes increased the risk of GC compared with the Gln/Gln genotype (P=0.049 and P=0.041, respectively; adjusted OR, 1.32 and 2.13, respectively; 95% CI, 1.00‐1.73 and 1.03-4.39, respectively). Compared with the Gln/Gln genotype, the LMP7-145 Gln/Lys and Lys/Lys variants of the LMP7 gene were also associated with increased susceptibility to GC (P=0.017; adjusted OR, 1.38; 95% CI, 1.06‐1.80). Haplotype analysis revealed that the LMP2 (Arg)-LMP7 (Lys) haplotype was associated with increased risk of GC (P=0.013, adjusted OR=1.34, 95% CI=1.06‐1.70). Stratified analysis revealed that the association between the risk of GC and the variant genotypes of LMP7-145 was stronger in older individuals (>59 years), males and non-smokers. However, no association between the LMP2-60 polymorphism and the risk of GC was observed. The present results suggest that the LMP7-145 genetic variant contributes to increased susceptibility to GC, and the Lys allele is an independent risk factor for GC. Introduction Gastric cancer (GC) remains the second leading cause of cancer-associated mortality worldwide (1,2), and approximately one-half of worldwide gastric cancer cases occur in China (3). Similar to other malignancies, the mechanism of gastric carcinogenesis involves a complex multi-stage and multi-factorial process that depends on gene-environment interactions (4). In previous epidemiological studies, genetic factors were demonstrated to play an important role in the development of gastric cancer (5-8). The expression of human leukocyte antigen (HLA) class I antigens on the surface of tumor cells is critical for the recognition of these cells by antigen‐specific cytotoxic T lymphocytes (CTLs), not only for the initiation of CTL‐associated inflammation but also for the anticancer immune response. An HLA‐class I restricted immune response has been reported to eliminate GC cells, and the expression of HLA‐class I antigens may be essential for the host immune response against cancer (9). Furthermore, downregulation of the expression of the HLA‐class I antigen in GC is associated with tumor progression and tumor histology (10). Therefore, HLA‐class I antigens may play a crucial role in the development and progression of GC. Several steps lead to the generation of the tumor antigen‐derived peptides that are presented by HLA class I antigens to cognate CTLs. In particular, tumor antigens are degraded into short peptides by the proteasome and immunoproteasome subunits low molecular weight protein (LMP)2 and LMP7. The resulting peptides are transported into the endoplasmic reticulum (ER) lumen by transporter associated with antigen presentation (TAP). In the ER, newly synthesized HLA class I heavy chains assemble with β2-microglobulin and peptides. Upon peptide binding, the HLA class I heterotrimeric complex is released from the ER and transported to the cell surface via the constitutive secretory pathway (11,12). Therefore, the integrality of LMP2 and LMP7 function plays an important role in the processing of GC cell antigens. The present study hypothesized that the processing of gastric tumor antigens may be influenced by structural differences encoded by the LMP alleles. Several studies have reported an association between the genetic variants of Arg to His substitution at codon 60 of Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study XIANG MA1*, CHAO YANG1*, RAN TANG1*, ZEKUAN XU1, ZHIHONG ZHANG2, YOUNAN WANG1, JINGJING ZHANG1,3 and LI YANG1 Departments of 1General Surgery and 2Pathology, The First Affiliated Hospital of Nanjing Medical University; 3Jiangsu Province Academy of Clinical Medicine, Institute of Tumor Biology, Nanjing, Jiangsu 210029, P.R. China Received June 23, 2014; Accepted April 8, 2015 DOI: 10.3892/ol.2015. 3154 Correspondence to: Dr Li Yang, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, P.R. China E-mail: pwkyangli@163.com *Contributed equally