ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma (original) (raw)

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State Key Laboratory of Molecular Oncology

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State Key Laboratory of Molecular Oncology

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Department of Pathology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

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Beijing 100021

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China

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State Key Laboratory of Molecular Oncology

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Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute

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Yangquan 045000, Shanxi Province

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China

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Center of Basic Medical Sciences, Navy General Hospital

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Beijing 100048

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China

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Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute

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Yangquan 045000, Shanxi Province

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China

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State Key Laboratory of Molecular Oncology

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Department of Oncological Surgery, Yangquan Cancer Prevention and Treatment Institute

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Yangquan 045000, Shanxi Province

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China

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State Key Laboratory of Molecular Oncology

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Revision received:

30 December 2013

Accepted:

25 January 2014

Published:

07 February 2014

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Yulin Sun, Ni Shi, Haizhen Lu, Jinqiang Zhang, Yulong Ma, Yuanyuan Qiao, Yonghong Mao, Kun Jia, Lifen Han, Fang Liu, Hongxia Li, Zhengwei Lin, Xinmin Li, Xiaohang Zhao, ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma, Carcinogenesis, Volume 35, Issue 9, September 2014, Pages 1941–1950, https://doi.org/10.1093/carcin/bgu043
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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.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Topic:

• genes
• genome
• squamous cell carcinoma, esophageal
• mrp4 protein, human
• amplification
• copy number polymorphism

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