title: ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is the eighth most common cause of cancer-related death worldwide. However, previous genome-wide single nucleotide polymorphism association analyses have not explained the high heritability associated with ESCC. In this study, we performed genome-wide copy number variation (CNV) analysis on 128 discordant sibling pairs to identify novel genes that contribute to ESCC susceptibility. A total of 57 774 individual CNVs were identified, and an interactive network of common CNV-associated genes was constructed, which showed that several ABC transporter genes contain CNVs in ESCC patients. Independent validation of a CNV at 13q32.1 in 1048 northern Chinese Han subjects demonstrated that the amplification of ABCC4 significantly correlated with ESCC risk [odds ratio: 3.36 (1.65-7.93), P = 0.0013]. Immunohistochemistry staining suggested that high copy numbers correlated with increased protein levels. High expression of ABCC4 was an independent poor prognostic factor for ESCC [relative risk: 1.73 (1.10-2.73), P = 0.0181]. The CNV region showed strong enhancer activity. Furthermore, inhibition of ABCC4 protein in ESCC cells decreased cell proliferation and motility via the inhibition of COX-2, PGE2 receptors and c-Myc expression; AKT, extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation; and β-catenin nuclear translocation in ESCC cells. In conclusion, the CNV at 13q32.1 is associated with ESCC susceptibility, and a gene within this locus, ABCC4, activates the oncogenic pathways in ESCC and thus facilitates cancer cell development and progression. A direct genetic contribution of ESCC risk through CNV common variants was determined in this study, and ABCC4 might therefore have predictive and therapeutic potential for ESCC.
authors: State Key Laboratory of Molecular Oncology and.
authors: Yulin
authors: Y
authors: Sun
authors: State Key Laboratory of Molecular Oncology and.
authors: Ni
authors: N
authors: Shi
authors: Department of Pathology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors: Haizhen
authors: H
authors: Lu
authors: State Key Laboratory of Molecular Oncology and.
authors: Jinqiang
authors: J
authors: Zhang
authors: Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute, Yangquan 045000, Shanxi Province, China.
authors: Yulong
authors: Y
authors: Ma
authors: Center of Basic Medical Sciences, Navy General Hospital, Beijing 100048, China.
authors: Yuanyuan
authors: Y
authors: Qiao
authors: Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute, Yangquan 045000, Shanxi Province, China.
authors: Yonghong
authors: Y
authors: Mao
authors: State Key Laboratory of Molecular Oncology and.
authors: Kun
authors: K
authors: Jia
authors: Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute, Yangquan 045000, Shanxi Province, China.
authors: Lifen
authors: L
authors: Han
authors: State Key Laboratory of Molecular Oncology and.
authors: Fang
authors: F
authors: Liu
authors: Shanxi Population and Family Planning Science Research Institute, Taiyuan 030006, Shanxi Province, China and.
authors: Hongxia
authors: H
authors: Li
authors: State Key Laboratory of Molecular Oncology and.
authors: Zhengwei
authors: Z
authors: Lin
authors: Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA zhaoxh@cicams.ac.cn xinminli@mednet.ucla.edu.
authors: Xinmin
authors: X
authors: Li
authors: State Key Laboratory of Molecular Oncology and Center of Basic Medical Sciences, Navy General Hospital, Beijing 100048, China, zhaoxh@cicams.ac.cn.
authors: Xiaohang
authors: X
authors: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D056915:DNA Copy Number Variations; D004742:Enhancer Elements, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011379:Prognosis; D060066:Protein Interaction Maps; D012306:Risk
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human