title: Co-expression network analysis identifies Spleen Tyrosine Kinase (SYK) as a candidate oncogenic driver in a subset of small-cell lung cancer.
abstract: BACKGROUND
  Oncogenic mechanisms in small-cell lung cancer remain poorly understood leaving this tumor with the worst prognosis among all lung cancers. Unlike other cancer types, sequencing genomic approaches have been of limited success in small-cell lung cancer, i.e., no mutated oncogenes with potential driver characteristics have emerged, as it is the case for activating mutations of epidermal growth factor receptor in non-small-cell lung cancer. Differential gene expression analysis has also produced SCLC signatures with limited application, since they are generally not robust across datasets. Nonetheless, additional genomic approaches are warranted, due to the increasing availability of suitable small-cell lung cancer datasets. Gene co-expression network approaches are a recent and promising avenue, since they have been successful in identifying gene modules that drive phenotypic traits in several biological systems, including other cancer types.
  
  
  RESULTS
  We derived an SCLC-specific classifier from weighted gene co-expression network analysis (WGCNA) of a lung cancer dataset. The classifier, termed SCLC-specific hub network (SSHN), robustly separates SCLC from other lung cancer types across multiple datasets and multiple platforms, including RNA-seq and shotgun proteomics. The classifier was also conserved in SCLC cell lines. SSHN is enriched for co-expressed signaling network hubs strongly associated with the SCLC phenotype. Twenty of these hubs are actionable kinases with oncogenic potential, among which spleen tyrosine kinase (SYK) exhibits one of the highest overall statistical associations to SCLC. In patient tissue microarrays and cell lines, SCLC can be separated into SYK-positive and -negative. SYK siRNA decreases proliferation rate and increases cell death of SYK-positive SCLC cell lines, suggesting a role for SYK as an oncogenic driver in a subset of SCLC.
  
  
  CONCLUSIONS
  SCLC treatment has thus far been limited to chemotherapy and radiation. Our WGCNA analysis identifies SYK both as a candidate biomarker to stratify SCLC patients and as a potential therapeutic target. In summary, WGCNA represents an alternative strategy to large scale sequencing for the identification of potential oncogenic drivers, based on a systems view of signaling networks. This strategy is especially useful in cancer types where no actionable mutations have emerged.
authors.forename: Akshata R
authors.initials: AR
authors.lastname: Udyavar
authors.forename: Megan D
authors.initials: MD
authors.lastname: Hoeksema
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Clark
authors.forename: Yong
authors.initials: Y
authors.lastname: Zou
authors.forename: Zuojian
authors.initials: Z
authors.lastname: Tang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.forename: Alexander
authors.initials: A
authors.lastname: Statnikov
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Liebler
authors.forename: John
authors.initials: J
authors.lastname: Field
authors.forename: Rosana
authors.initials: R
authors.lastname: Eisenberg
authors.forename: Lourdes
authors.initials: L
authors.lastname: Estrada
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.forename: Vito
authors.initials: V
authors.lastname: Quaranta
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology*; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase