ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma
ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma
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ABCC4拷贝数变异与食管鳞状细胞癌易感性相关
DOI：
10.1093/carcin/bgu043
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发表时间：
2014-09-01
期刊：
影响因子：
4.7
通讯作者：
Zhao, Xiaohang
中科院分区：
文献类型：
--
作者：
Sun, Yulin;Shi, Ni;Zhao, Xiaohang
食管鳞状细胞癌（ESCC）是全球癌症相关死亡的第八大常见原因。然而，之前的全基因组单核苷酸多态性关联分析尚未解释与食管鳞癌相关的高遗传力。在这项研究中，我们对 128 对不一致的兄弟姐妹进行了全基因组拷贝数变异 (CNV) 分析，以确定导致 ESCC 易感性的新基因。共鉴定出 57 774 个个体 CNV，并构建了常见 CNV 相关基因的交互网络，表明 ESCC 患者中多个 ABC 转运蛋白基因含有 CNV。对 1048 名中国北方汉族受试者 13q32.1 处 CNV 的独立验证表明，ABCC4 的扩增与 ESCC 风险显着相关 [比值比：3.36 (1.65-7.93)，P = 0.0013]。免疫组织化学染色表明高拷贝数与蛋白质水平增加相关。 ABCC4高表达是ESCC的独立不良预后因素[相对风险：1.73（1.10-2.73），P = 0.0181]。 CNV 区域显示出很强的增强子活性。此外，抑制 ESCC 细胞中的 ABCC4 蛋白可通过抑制 COX-2、PGE(2) 受体和 c-Myc 表达来减少细胞增殖和运动。 AKT、细胞外信号调节激酶和cAMP反应元件结合蛋白磷酸化；和 ESCC 细胞中的β-连环蛋白核转位。总之，13q32.1 的 CNV 与 ESCC 易感性相关，该位点内的基因 ABCC4 激活 ESCC 中的致癌途径，从而促进癌细胞的发育和进展。本研究确定了 CNV 常见变异对 ESCC 风险的直接遗传贡献，因此 ABCC4 可能具有 ESCC 的预测和治疗潜力。
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, PGE(2) receptors and c-Myc expression; AKT, extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation; and beta-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.