title: Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung.
abstract: OBJECTIVE
  Chromosome 3q26-29 is a critical region of genomic amplification in lung squamous cell carcinomas (SCC). Identification of candidate drivers in this region could help uncover new mechanisms in the pathogenesis and potentially new targets in SCC of the lung.
  
  
  METHODS
  We conducted a meta-analysis of seven independent datasets containing a total of 593 human primary SCC samples to identify consensus candidate drivers in 3q26-29 amplicon. Through integrating protein-protein interaction network information, we further filtered for candidates that may function together in a network. Computationally predicted candidates were validated using RNA interference (RNAi) knockdown and cell viability assays. Clinical relevance of the experimentally supported drivers was evaluated in an independent cohort of 52 lung SCC patients using survival analysis.
  
  
  RESULTS
  The meta-analysis identified 20 consensus candidates, among which four (SENP2, DCUN1D1, DVL3, and UBXN7) are involved in a small protein-protein interaction network. Knocking down any of the four proteins led to cell growth inhibition of the 3q26-29-amplified SCC. Moreover, knocking down of SENP2 resulted in the most significant cell growth inhibition and downregulation of DCUN1D1 and DVL3. Importantly, a gene expression signature composed of SENP2, DCUN1D1, and DVL3 stratified patients into subgroups with different response to adjuvant chemotherapy.
  
  
  CONCLUSIONS
  Together, our findings show that SENP2, DCUN1D1, and DVL3 are candidate driver genes in the 3q26-29 amplicon of SCC, providing novel insights into the molecular mechanisms of disease progression and may have significant implication in the management of SCC of the lung.
authors.affiliation: Authors' Affiliations: Department of Biomedical Informatics, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine; and Veterans Affairs, Tennessee Valley Health Care Systems, Nashville, Tennessee.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Megan D
authors.initials: MD
authors.lastname: Hoeksema
authors.forename: Yong
authors.initials: Y
authors.lastname: Zou
authors.forename: Allan V
authors.initials: AV
authors.lastname: Espinosa
authors.forename: S M Jamshedur
authors.initials: SM
authors.lastname: Rahman
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002893:Chromosomes, Human, Pair 3; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D009857:Oncogenes; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents
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