title: PathScan: a tool for discerning mutational significance in groups of putative cancer genes.
abstract: BACKGROUND
  The expansion of cancer genome sequencing continues to stimulate development of analytical tools for inferring relationships between somatic changes and tumor development. Pathway associations are especially consequential, but existing algorithms are demonstrably inadequate.
  
  
  METHODS
  Here, we propose the PathScan significance test for the scenario where pathway mutations collectively contribute to tumor development. Its design addresses two aspects that established methods neglect. First, we account for variations in gene length and the consequent differences in their mutation probabilities under the standard null hypothesis of random mutation. The associated spike in computational effort is mitigated by accurate convolution-based approximation. Second, we combine individual probabilities into a multiple-sample value using Fisher-Lancaster theory, thereby improving differentiation between a few highly mutated genes and many genes having only a few mutations apiece. We investigate accuracy, computational effort and power, reporting acceptable performance for each.
  
  
  RESULTS
  As an example calculation, we re-analyze KEGG-based lung adenocarcinoma pathway mutations from the Tumor Sequencing Project. Our test recapitulates the most significant pathways and finds that others for which the original test battery was inconclusive are not actually significant. It also identifies the focal adhesion pathway as being significantly mutated, a finding consistent with earlier studies. We also expand this analysis to other databases: Reactome, BioCarta, Pfam, PID and SMART, finding additional hits in ErbB and EPHA signaling pathways and regulation of telomerase. All have implications and plausible mechanistic roles in cancer. Finally, we discuss aspects of extending the method to integrate gene-specific background rates and other types of genetic anomalies.
  
  
  BACKGROUND
  PathScan is implemented in Perl and is available from the Genome Institute at: http://genome.wustl.edu/software/pathscan.
authors.affiliation: The Genome Institute, Washington University, St Louis, MO 63108, USA. mwendl@wustl.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.forename: John W
authors.initials: JW
authors.lastname: Wallis
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D052138:Genes, Neoplasm; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D009154:Mutation; D012984:Software