Genetic variability in LMP2 and LMP7 is associated with the risk of esophageal squamous cell carcinoma in the Kazakh population but is not associated with HPV infection.

Lan Yang,Lijuan Pang,Fei Wu,Yu Ji,Ling Chen,Feng Li,Xiaobin Cui,Yutao Wei,Jinfang Jiang,Jianming Hu,Mei Li,Yunzhao Chen,Maria Lina Tornesello

doi:10.1371/journal.pone.0186319

Abstract

The Kazakh population in Xinjiang Province in northwestern China exhibits a high incidence of esophageal squamous cell carcinoma (ESCC). Although the etiology of esophageal carcinoma (EC) has not been elucidated, there are reports of the involvement of an immunologic mechanism. In the current study, 268 Kazakh ESCC patients and 500 age- and sex-matched control subjects were recruited. DNA was extracted from paraffin-embedded tumor specimens from the patients and peripheral blood lymphocytes from the controls and used for LMP2/LMP7 genotyping. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect LMP2/LMP7 gene single-nucleotide polymorphisms (SNPs). We found a clear increased risk of ESCC in the Kazakh population for the heterozygous LMP2 R/C genotype and the homozygous C/C genotype (OR = 1.470, 95%CI = 1.076–2.008, p = 0.015 forLMP2R/C; OR = 2.048, 95% CI = 1.168–3.591, p = 0.011 for LMP2 C/C). Conversely, the heterozygous LMP7 Q/K polymorphism was found to decrease the risk of ESCC in this population (OR = 0.421, 95% CI = 0.286–0.621, p = 8.83×10−6). Moreover, LMP2 R/C+C/C genotype was associated with increased tumor invasion depth (p = 0.041). Haplotype analysis showed that haplotype A, which includes wild-type homozygous LMP2/TAP1 and mutant LMP7, decreases susceptibility to ESCC in the Kazakh population; in contrast, haplotype E, which includes wild-type homozygous LMP2/LMP7/TAP1, acts as a risk factor for increased susceptibility to ESCC. This is the first study to report that the heterozygous LMP2 R/C and homozygous C/C genotypes increase susceptibility to ESCC in the Kazakh population and that the heterozygous LMP7 Q/K genotype decreases susceptibility to ESCC in this population. Nevertheless, neither LMP2 nor LMP7 was associated with human papillomavirus (HPV) infection. Understanding LMP2/LMP7 genetic variability will provide a new therapeutic perspective for Kazakh patients with ESCC.

Highlights

Esophageal carcinoma (EC) is considered one of the most malignant cancers worldwide [1,2,3,4,5]
We used the expression of quantitative trait loci data which have been reported to study the effects of singlenucleotide polymorphisms (SNPs) locus of LMP2/LMP7 gene on gene expression, the results showed that SNP locus of LMP2 in esophageal tissues affected the expression of LMP2
The results showed that haplotype A, which includes wild-type homozygous LMP2/TAP1 and mutant LMP7, decreases susceptibility to esophageal squamous cell carcinoma (ESCC) in the Kazakh population (OR = 0.37, 95%confidence intervals (CIs) = 0.23–0.59, p

Summary

Introduction

Esophageal carcinoma (EC) is considered one of the most malignant cancers worldwide [1,2,3,4,5]. More than 90% of ECs are either esophageal squamous cell carcinomas (ESCCs) or adenocarcinomas (EACs). In western countries and areas with a low incidence of ESCC, excess alcohol intake in combination with smoking greatly increases the risk of EC [8]. Diets deficient in vitamins as well as intake of carcinogens have been speculated as risk factors for ESCC [9]. The Kazakh population, a minority group in the Xinjiang region of northwest China that still maintains its traditional way of life (such as living in a dry, hot climate and consuming a vitamin-deficient diet), exhibits the highest ESCC mortality rate among different minorities in China. Many genetic variations, especially polymorphisms, are prevalent in the Kazakh population, some of which are associated with an increased risk of cancer [11]

Methods

Results

Conclusion