title: A gene signature based method for identifying subtypes and subtype-specific drivers in cancer with an application to medulloblastoma.
abstract: BACKGROUND
  Subtypes are widely found in cancer. They are characterized with different behaviors in clinical and molecular profiles, such as survival rates, gene signature and copy number aberrations (CNAs). While cancer is generally believed to have been caused by genetic aberrations, the number of such events is tremendous in the cancer tissue and only a small subset of them may be tumorigenic. On the other hand, gene expression signature of a subtype represents residuals of the subtype-specific cancer mechanisms. Using high-throughput data to link these factors to define subtype boundaries and identify subtype-specific drivers, is a promising yet largely unexplored topic.
  
  
  RESULTS
  We report a systematic method to automate the identification of cancer subtypes and candidate drivers. Specifically, we propose an iterative algorithm that alternates between gene expression clustering and gene signature selection. We applied the method to datasets of the pediatric cerebellar tumor medulloblastoma (MB). The subtyping algorithm consistently converges on multiple datasets of medulloblastoma, and the converged signatures and copy number landscapes are also found to be highly reproducible across the datasets. Based on the identified subtypes, we developed a PCA-based approach for subtype-specific identification of cancer drivers. The top-ranked driver candidates are found to be enriched with known pathways in certain subtypes of MB. This might reveal new understandings for these subtypes.
  
  
  CONCLUSIONS
  Our study indicates that subtype-signature defines the subtype boundaries, characterizes the subtype-specific processes and can be used to prioritize signature-related drivers.
authors.forename: Peikai
authors.initials: P
authors.lastname: Chen
authors.forename: Yubo
authors.initials: Y
authors.lastname: Fan
authors.forename: Tsz-kwong
authors.initials: TK
authors.lastname: Man
authors.forename: Y S
authors.initials: YS
authors.lastname: Hung
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
mesh_terms: D000465:Algorithms; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D016000:Cluster Analysis; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D015996:Survival Rate