PathScan: a tool for discerning mutational significance in groups of putative cancer genes.
Bioinformatics
; 27(12): 1595-602, 2011 Jun 15.
Article
en En
| MEDLINE
| ID: mdl-21498403
ABSTRACT
MOTIVATION 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.AVAILABILITY:
PathScan is implemented in Perl and is available from the Genome Institute at http//genome.wustl.edu/software/pathscan.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Adenocarcinoma
/
Genes Relacionados con las Neoplasias
/
Neoplasias Pulmonares
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioinformatics
Asunto de la revista:
INFORMATICA MEDICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos