Variations in the MHC Region Confer Risk to Esophageal Squamous Cell Carcinoma on the Subjects from High-Incidence Area in Northern China

Abstract

BackgroundThe human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity. Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC). Our previous genome-wide association study (GWAS) has indicated that the MHC region may confer important risk loci for ESCC, but without further fine mapping. The aim of this study is to further identify the risk loci in the MHC region for ESCC in Chinese population.MethodsConditional logistic regression analysis (CLRA) was performed on 24 single nucleotide polymorphisms (SNPs) within the MHC region, which were obtained from the genetically matched 937 cases and 692 controls of Chinese Han population. The identified promising SNPs were further correlated with clinical and clinicopathology characteristics. Immunohistochemistry was performed to explore the protein expression pattern of the related genes in ESCC and neighboring normal tissues.ResultsOf the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36–2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50–0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64–0.86). These three SNPs were located at the genes of HLA-DQA1, TRIM27, and DPCR1, respectively. Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009). The positive immunostaining rates both for HLA-DQA1 and TRIM27 were much higher in ESCC tissues than in neighboring normal tissues (69.4% vs. 26.8% for HLA-DQA1 and 77.6% vs. 47.8% for TRIM27, P<0.001). Furthermore, the overexpression of HLA-DQA1 is correlated significantly with age (P = 0.001) and family history (P<0.001).ConclusionThis study for the first time provides evidence that multiple genetic factors within the MHC region confer risk to ESCC on the subjects from high-risk area in northern China.

The Relationship Between Environmental Exposure and Genetic Architecture of the 2q33 Locus With Esophageal Cancer in South Africa

“…This study investigated the association between common genetic polymorphisms at 2q33 and 6p21 and the risk of ESCC in two South African populations. These variants were previously reported to be associated with higher risk for both ESCC and other cancer types in the Chinese population (Shen et al, 2014; Zhang et al, 2017; Zhao et al, 2017). Our analysis revealed three SNPs at 2q33 (rs10931936, rs7578456, rs2244438) that conferred an increased risk of ESCC in the Mixed Ancestry population, thus replicating the association signals identified in the Chinese study (Zhao et al, 2017).…”

“…For the 2q33 locus, we selected five SNPs (rs3769823, rs10931936, rs13016963, rs7578456, and rs2244438) that were significantly associated (p < 0.05) with both esophageal and lung cancer risk in a northern Chinese population (Zhao et al, 2017). For the 6p21 locus, the selected SNPs were those with strongest evidence of association from published studies of ESCC in northern China (Shen et al, 2014; Zhang et al, 2017). These risk variants were investigated for their frequency in sample populations from the 1000 Genomes Project Phase 3 1 .…”

“…These variants are therefore strong candidates for the study of pivotal biological mechanisms and pleiotropic effects associated with carcinogenesis. Previous GWAS and case-control studies have also identified the human major histocompatibility complex (MHC) region on chromosome 6p21 as a novel susceptibility locus for ESCC in high-risk populations from northern China (Wu et al, 2011; Shen et al, 2014; Zhang et al, 2017). Of these, the variant rs10484761 located upstream of the UNC5CL gene was found to be significantly associated with increased risk of ESCC in the Mixed Ancestry South African population (Bye et al, 2012).…”

Cancer Characteristic Gene Selection via Sample Learning Based on Deep Sparse Filtering

“…Shen et al . have performed the first GWAS (Genome-wide Association Study) of esophageal squamous cell carcinoma in the MHC (Major Histocompatibility Complex) region on the subjects from high risk areas in northern China and found three important independent susceptibility loci containing three biologically interesting candidate genes, i.e., HLA-DQA1, TRIM27 and DPCR1 39 . Li et al .…”

Whole-exome sequencing identifies variants in invasive pituitary adenomas

“…DPCR1, located between major histocompatibility complex (MHC), class I (HLA)-B and HLA-A on chromosome 6p21.33, is classified as one of the HLA molecules. The DPCR1 gene may contain markers for diagnosis of diffuse pan-bronchiolitis, a bronchiolar disease that affects human airways ( 34 ). To fully escape the immune system, cancer cells typically mutate to decrease the expression of antigens, lose expression of HLA proteins or employ an aberrant antigen processing pathway ( 35 ).…”