title: A multilevel pan-cancer map links gene mutations to cancer hallmarks.
abstract: BACKGROUND
  A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested. This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.
  
  
  METHODS
  We created a map that connects genes to cancer hallmarks via signaling pathways. We projected gene mutation and focal copy number data from various cancer types onto this map. We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.
  
  
  RESULTS
  Our analysis showed that although the genetic fingerprint of tumor types could be very different, there were less variations at the level of hallmarks, consistent with the idea that different genetic alterations have similar functional outcomes. Additionally, we showed how the multilevel map could help to clarify the role of infrequently mutated genes, and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways, whereas many co-occurring gene mutations were associated with hallmark characteristics.
  
  
  CONCLUSIONS
  Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.
authors.affiliation: Institute for Systems Biology, Seattle, WA, 98109, USA. theo.knijnenburg@systemsbiology.org.
authors.forename: Theo A
authors.initials: TA
authors.lastname: Knijnenburg
authors.affiliation: Bioinformatics and Statistics, Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. t.bismeijer@nki.nl.
authors.forename: Tycho
authors.initials: T
authors.lastname: Bismeijer
authors.affiliation: Bioinformatics and Statistics, Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. l.wessels@nki.nl.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Institute for Systems Biology, Seattle, WA, 98109, USA. ilya.shmulevich@systemsbiology.org.
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
mesh_terms: D023281:Genomics; D006801:Humans; D009154:Mutation; D009369:Neoplasms; D009385:Neoplastic Processes; D015398:Signal Transduction