Genome-wide copy number variation analysis identified ANO1 as a novel oncogene and prognostic biomarker in esophageal squamous cell cancer

• Published in: Carcinogenesis (New York) Vol. 40; no. 10; pp. 1198 - 1208
• Main Authors: Yu, Yue, Cao, Jing, Wu, Weibing, Zhu, Quan, Tang, Yu, Zhu, Chengxiang, Dai, Juncheng, Li, Zhihua, Wang, Jun, Xue, Lei, Zhen, Fuxi, Liu, Jinyuan, Huang, Chenjun, Zhao, Fei, Zhou, Yue, Wen, Wei, Pan, Xianglong, Wei, Haixing, Zhu, Yining, He, Yaozhou, Que, Jun, Wang, Wei, Luo, Jinhua, Xu, Jing, Chen, Liang
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 16.10.2019
• Subjects: Animals; Anoctamin-1 - genetics; Anoctamin-1 - metabolism; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Cycle; Cell Proliferation; DNA Copy Number Variations; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncogenes; Prognosis; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgz077

Abstract Copy number variations (CNVs) represent one of the most common genomic alterations. This study aimed to evaluate the roles of genes within highly aberrant genome regions in the prognosis of esophageal squamous cell cancer (ESCC). Exome sequencing data from 81 paired ESCC tissues were used to screen aberrant genomic regions. The associations between CNVs and gene expression were evaluated using gene expression data from the same individuals. Then, an RNA expression array profile from 119 ESCC samples was adopted for differential gene expression and prognostic analyses. Two independent ESCC cohorts with 315 subjects were further recruited to validate the prognostic value using immunohistochemistry tests. Finally, we explored the potential mechanism of our identified novel oncogene in ESCC. In total, 2003 genes with CNVs were observed, of which 76 genes showed recurrent CNVs in more than three samples. Among them, 32 genes were aberrantly expressed in ESCC tumor tissues and statistically correlated with CNVs. Strikingly, 4 (CTTN, SHANK2, INPPL1 and ANO1) of the 32 genes were significantly associated with the prognosis of ESCC patients. Patients with a positive expression of ANO1 had a poorer prognosis than ANO1 negative patients (overall survival rate: 42.91% versus 26.22% for ANO1−/+ samples, P < 0.001). Functionally, ANO1 promoted ESCC cell proliferation, migration and invasion by activating transforming growth factor-β pathway. Knockdown of ANO1 significantly inhibited tumor progression in vitro and in vivo. In conclusion, ANO1 is a novel oncogene in ESCC and may serve as a prognostic biomarker for ESCC.