ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma.
Carcinogenesis
; 35(9): 1941-50, 2014 Sep.
Article
in En
| MEDLINE
| ID: mdl-24510239
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 ß-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.
Full text:
1
Database:
MEDLINE
Main subject:
Esophageal Neoplasms
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Carcinoma, Squamous Cell
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Multidrug Resistance-Associated Proteins
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DNA Copy Number Variations
Type of study:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
/
Middle aged
Language:
En
Year:
2014
Type:
Article