Esophageal squamous cell carcinoma (ESCC) is one of the most common
cancers worldwide with poor prognosis. Thus, identification of predictive
biomarkers for early diagnosis and intervention is needed to improve patients' survival. Research shows that heritable mutations, such as single nucleotide polymorphisms (SNPs), contribute to human
cancer susceptibility significantly. However, the association of copy number variations (CNVs), another major source of genetic variation, with ESCC risk remains poorly clarified. In this study, we aimed to identify ESCC risk-related CNVs based on candidate-gene strategy in a case-control study. A meta-analysis was first performed to identify the most variable chromosome regions of ESCC tissues. Bioinformatic analysis and dual-
luciferase reporter assays were carried out to evaluate the properties of all recorded CNVs located on these regions. Six candidate CNVs located within well-known oncogenes and detoxification-associated
enzymes were enrolled in the final analysis. A newly developed multiplex gene copy number quantitation method AccuCopy(TM) was employed to simultaneously genotype all six candidate sites in 404 ESCC patients and 402
cancer-free controls from Southwest China, and in 42 ESCC tissues. qRT-PCR was performed to measure
UGT2B28 mRNA in cancerous and corresponding normal tissues. Unconditional logistic regression was applied to test association between germline CNV genotypes and ESCC risk. Relationship between germline copy number variation and somatic copy number alterations was further analyzed. Finally we found that copy number loss of
UDP-glucuronosyltransferase family 2,
polypeptide B28 (
UGT2B28) and gain of
plectin (PLEC) conferred increased ESCC risk (Adjusted OR = 2.085, 95% CI = 1.493-2.912, P < 0.001 for
UGT2B28. Adjusted OR = 3.725, 95% CI = 1.026-13.533, P = 0.046 for PLEC).
mRNA level was lower in
UGT2B28 loss genotyped esophageal tissues than in two-copy tissues, indicating that
UGT2B28 loss genotypes modify ESCC susceptibility perhaps by decreasing
UGT2B28 expression level and
enzyme activity. In addition, an association was drawn between germline copy number variations and somatic alterations for PLEC, UGT2B17 and
UGT2B28, but not for other candidate loci.