Integrative analysis of copy number and transcriptional expression profiles in esophageal cancer to identify a novel driver gene for therapy

An increasing amount of evidence has highlighted the critical roles that copy number variants play in cancer progression. Here, we systematically analyzed the copy number alterations and differentially transcribed genes. Integrative analysis of the association between copy number variants and differential gene expression suggested that copy number variants will lead to aberrant expression of the corresponding genes. We performed a KEGG pathway and GO analysis, which revealed that cell cycle may have an effective role in the progression of esophageal cancer. FAM60A was then screened out as a potential prognostic factor through survival analysis and correlation analysis with clinical-pathological parameters. We subsequently showed that silencing of FAM60A could inhibit esophageal carcinoma tumor cell growth, migration and invasion in vitro. Through the bioinformatic analysis, we predict that FAM60A may act as a transcriptional factor to regulate genes that are correlated with each cell cycle. In summary, we comprehensively analyzed copy number segments and transcriptional expression profiles, which provided a novel approach to identify clinical biomarkers and therapeutic targets of esophageal carcinoma.

[1]  E. Bernstein,et al.  NR2F1 controls tumor cell dormancy via SOX9 and RARβ driven quiescence programs , 2014, Nature Communications.

[2]  Mihaela E. Sardiu,et al.  Human Family with Sequence Similarity 60 Member A (FAM60A) Protein: a New Subunit of the Sin3 Deacetylase Complex* , 2012, Molecular & Cellular Proteomics.

[3]  S. Ferrari,et al.  Author contributions , 2021 .

[4]  T. Yen,et al.  Somatic copy number alterations detected by ultra-deep targeted sequencing predict prognosis in oral cavity squamous cell carcinoma , 2015, Oncotarget.

[5]  D. Lin,et al.  Genetic alteration profiling of patients with resected squamous cell lung carcinomas , 2016, Oncotarget.

[6]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[7]  Kyusam Choi,et al.  Homeobox Msx1 interacts with p53 tumor suppressor and inhibits tumor growth by inducing apoptosis. , 2005, Cancer research.

[8]  Michael Wigler,et al.  A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions , 2012, Proceedings of the National Academy of Sciences.

[9]  L. Tao,et al.  CYB5D2 displays tumor suppression activities towards cervical cancer. , 2016, Biochimica et biophysica acta.

[10]  Federación de Sociedades Españolas de Oncología.  Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. , 2005 .

[11]  S. Miyano,et al.  An Integrative Analysis to Identify Driver Genes in Esophageal Squamous Cell Carcinoma , 2015, PloS one.

[12]  P. Deloukas,et al.  Signatures of mutation and selection in the cancer genome , 2010, Nature.

[13]  A. Bode,et al.  HOI-02 induces apoptosis and G2-M arrest in esophageal cancer mediated by ROS , 2015, Cell Death and Disease.

[14]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[15]  W. Mao,et al.  Neoadjuvant versus adjuvant treatment: which one is better for resectable esophageal squamous cell carcinoma? , 2012, World Journal of Surgical Oncology.

[16]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[17]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[18]  S. Franceschi,et al.  EPIDEMIOLOGY OF ESOPHAGEAL CANCER , 2013 .

[19]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[20]  Jiansheng Guo,et al.  Genomic analyses reveal FAM84B and the NOTCH pathway are associated with the progression of esophageal squamous cell carcinoma , 2016, GigaScience.

[21]  Ying Yuan,et al.  Identification of recurrent focal copy number variations and their putative targeted driver genes in ovarian cancer , 2016, BMC Bioinformatics.

[22]  Qiang Feng,et al.  Identification of genomic alterations in oesophageal squamous cell cancer , 2014, Nature.

[23]  M. Ichihara,et al.  GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region , 2005, Nucleic acids research.

[24]  Zhi-hua Chen,et al.  Kyoto Encyclopedia of Genes and Genomes were used for functional enrichment analysis of differentially expressed genes (DEGs). A protein‐protein interaction network was constructed, and the hub genes were subjected to module analysis and identification using Search Tool for the Retrieval , 2019 .

[25]  M. Caraglia,et al.  Histone deacetylase inhibitors: a new wave of molecular targeted anticancer agents. , 2007, Recent patents on anti-cancer drug discovery.

[26]  G. Mills,et al.  Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers. , 2015, Cancer cell.

[27]  C. Ponting,et al.  Family with Sequence Similarity 60A (FAM60A) Protein Is a Cell Cycle-fluctuating Regulator of the SIN3-HDAC1 Histone Deacetylase Complex* , 2012, The Journal of Biological Chemistry.

[28]  James Y. Dai,et al.  Copy number alterations detected by whole-exome and whole-genome sequencing of esophageal adenocarcinoma , 2015, Human Genomics.

[29]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[30]  H. Aburatani,et al.  Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. , 2016, Gastroenterology.

[31]  H. Stein,et al.  Oesophageal cancer—an overview , 2013, Nature Reviews Gastroenterology &Hepatology.

[32]  Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels , 2016, Oncotarget.

[33]  Q. Xue,et al.  Expression and prognostic role of c-Myb as a novel cell cycle protein in esophageal squamous cell carcinoma , 2013, Clinical and Translational Oncology.

[34]  Mark D. Johnson,et al.  Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes , 2013, Genome research.

[35]  Fang Liu,et al.  ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma. , 2014, Carcinogenesis.

[36]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[37]  J. Luketich,et al.  Oesophageal carcinoma , 2013, The Lancet.

[38]  J. Shendure,et al.  A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer , 2015, Nature Genetics.