{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T15:17:41Z","timestamp":1766157461374},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>\n               <jats:p>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\u2013Lancaster 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.<\/jats:p>\n               <jats:p>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.<\/jats:p>\n               <jats:p>Availability: PathScan is implemented in Perl and is available from the Genome Institute at: http:\/\/genome.wustl.edu\/software\/pathscan.<\/jats:p>\n               <jats:p>Contact: \u00a0mwendl@wustl.edu<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btr193","type":"journal-article","created":{"date-parts":[[2011,4,16]],"date-time":"2011-04-16T06:36:52Z","timestamp":1302935812000},"page":"1595-1602","source":"Crossref","is-referenced-by-count":76,"title":["PathScan: a tool for discerning mutational significance in groups of putative cancer genes"],"prefix":"10.1093","volume":"27","author":[{"given":"Michael C.","family":"Wendl","sequence":"first","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"John W.","family":"Wallis","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"Ling","family":"Lin","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"Cyriac","family":"Kandoth","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"Elaine R.","family":"Mardis","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"Richard K.","family":"Wilson","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"},{"name":"1 The Genome Institute, 2Department of Genetics, 3Department of Mathematics and 4Siteman Cancer Center, Washington University, St Louis, MO 63108, USA"}]}],"member":"286","published-online":{"date-parts":[[2011,4,14]]},"reference":[{"key":"2023012511151615200_B1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/nar\/28.1.263","article-title":"The Pfam protein families database","volume":"28","author":"Bateman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023012511151615200_B2","first-page":"289","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"2023012511151615200_B3","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature09744","article-title":"The genomic complexity of primary human prostate cancer","volume":"470","author":"Berger","year":"2011","journal-title":"Nature"},{"key":"2023012511151615200_B4","doi-asserted-by":"crossref","first-page":"20007","DOI":"10.1073\/pnas.0710052104","article-title":"Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma","volume":"104","author":"Beroukhim","year":"2007","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012511151615200_B5","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1214\/ss\/1009213286","article-title":"Interval estimation for a binomial proportion","volume":"16","author":"Brown","year":"2001","journal-title":"Stat. Sci."},{"key":"2023012511151615200_B6","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0008918","article-title":"Automated network analysis identifies core pathways in glioblastoma","volume":"5","author":"Cerami","year":"2010","journal-title":"PLoS One"},{"key":"2023012511151615200_B7","volume-title":"Introduction to Algorithms","author":"Cormen","year":"1990"},{"key":"2023012511151615200_B8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1371\/journal.pmed.1000024","article-title":"Survival-related profile, pathways, and transcription factors in ovarian cancer","volume":"6","author":"Crijns","year":"2009","journal-title":"PLoS Med."},{"key":"2023012511151615200_B9","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature07423","article-title":"Somatic mutations affect key pathways in lung adenocarcinoma","volume":"455","author":"Ding","year":"2008","journal-title":"Nature"},{"key":"2023012511151615200_B10","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/nature08989","article-title":"Genome remodelling in a basal\u2013like breast cancer metastasis and xenograft","volume":"464","author":"Ding","year":"2010","journal-title":"Nature"},{"key":"2023012511151615200_B11","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0014437","article-title":"Detecting cancer gene networks characterized by recurrent genomic alterations in a population","volume":"6","author":"Efroni","year":"2011","journal-title":"PLoS One"},{"key":"2023012511151615200_B12","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.2353\/ajpath.2009.090115","article-title":"Early dysregulation of cell adhesion and extracellular matrix pathways in breast cancer progression","volume":"175","author":"Emery","year":"2009","journal-title":"Am. J. Pathol."},{"key":"2023012511151615200_B13","volume-title":"An Introduction to Probability Theory and Its Applications","author":"Feller","year":"1968","edition":"3"},{"key":"2023012511151615200_B14","volume-title":"Statistical Methods for Research Workers","author":"Fisher","year":"1938","edition":"7"},{"key":"2023012511151615200_B15","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1126\/science.1138179","article-title":"Comment on \u2018the consensus coding sequences of human breast and colorectal cancers\u2019","volume":"317","author":"Forrest","year":"2007","journal-title":"Science"},{"key":"2023012511151615200_B16","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1126\/science.1138764","article-title":"Comment on \u2018the consensus coding sequences of human breast and colorectal cancers\u2019","volume":"317","author":"Getz","year":"2007","journal-title":"Science"},{"key":"2023012511151615200_B17","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-11-597","article-title":"Extending pathways and processes using molecular interaction networks to analyse cancer genome data","volume":"11","author":"Glaab","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2023012511151615200_B18","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1534\/genetics.105.044677","article-title":"Statistical analysis of pathogenicity of somatic mutations in cancer","volume":"173","author":"Greenman","year":"2006","journal-title":"Genetics"},{"key":"2023012511151615200_B19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nature05610","article-title":"Patterns of somatic mutation in human cancer genomes","volume":"446","author":"Greenman","year":"2007","journal-title":"Nature"},{"key":"2023012511151615200_B20","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/bioinformatics\/btm141","article-title":"Identifying the biologically relevant gene categories based on gene expression and biological data: an example on prostate cancer","volume":"23","author":"Huang","year":"2007","journal-title":"Bioinformatics"},{"key":"2023012511151615200_B21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ceb.2008.12.010","article-title":"ErbB receptors and signaling pathways in cancer","volume":"21","author":"Hynes","year":"2009","journal-title":"Curr. Opin. Cell Biol."},{"key":"2023012511151615200_B22","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nature03001","article-title":"Finishing the euchromatic sequence of the human genome","volume":"431","author":"International Human Genome Sequencing Consortium","year":"2004","journal-title":"Nature"},{"key":"2023012511151615200_B23","doi-asserted-by":"crossref","first-page":"D428","DOI":"10.1093\/nar\/gki072","article-title":"Reactome: a knowledgebase of biological pathways","volume":"33","author":"Joshi-Tope","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012511151615200_B24","doi-asserted-by":"crossref","first-page":"D355","DOI":"10.1093\/nar\/gkp896","article-title":"KEGG for representation and analysis of molecular networks involving diseases and drugs","volume":"38","author":"Kanehisa","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023012511151615200_B25","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1093\/biomet\/36.3-4.370","article-title":"The combination of probabilities arising from data in discrete distributions","volume":"36","author":"Lancaster","year":"1949","journal-title":"Biometrika"},{"key":"2023012511151615200_B26","doi-asserted-by":"crossref","first-page":"D229","DOI":"10.1093\/nar\/gkn808","article-title":"SMART 6: recent updates and new developments","volume":"37","author":"Letunic","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012511151615200_B27","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/nature07485","article-title":"DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome","volume":"456","author":"Ley","year":"2008","journal-title":"Nature"},{"key":"2023012511151615200_B28","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1101\/gr.6431107","article-title":"A multidimensional analysis of genes mutated in breast and colorectal cancers","volume":"17","author":"Lin","year":"2007","journal-title":"Genome Res."},{"key":"2023012511151615200_B29","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJMoa0903840","article-title":"Recurring mutations found by sequencing an acute myeloid leukemia genome","volume":"361","author":"Mardis","year":"2009","journal-title":"N. Eng. J. Med."},{"key":"2023012511151615200_B30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"BioCarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotech Softw. Internet Rep."},{"key":"2023012511151615200_B31","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1126\/science.1138773","article-title":"Response to comments on \u2018the consensus coding sequences of human breast and colorectal cancers\u2019","volume":"317","author":"Parmigiani","year":"2007","journal-title":"Science"},{"key":"2023012511151615200_B32","doi-asserted-by":"crossref","DOI":"10.2202\/1544-6115.1277","article-title":"TRAB: testing whether mutation frequencies are above an unknown background","volume":"7","author":"Parmigiani","year":"2008","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2023012511151615200_B33","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/nrc2806","article-title":"Eph receptors and ephrins in cancer: bidirectional signalling and beyond","volume":"10","author":"Pasquale","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"2023012511151615200_B34","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/biomet\/25.3-4.379","article-title":"On a method of determining whether a sample of size n supposed to have been drawn from a parent population having a known probability integral has probably been drawn at random","volume":"25","author":"Pearson","year":"1933","journal-title":"Biometrika"},{"key":"2023012511151615200_B35","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1126\/science.1138956","article-title":"Comment on \u2018the consensus coding sequences of human breast and colorectal cancers\u2019","volume":"317","author":"Rubin","year":"2007","journal-title":"Science"},{"key":"2023012511151615200_B36","doi-asserted-by":"crossref","first-page":"D674","DOI":"10.1093\/nar\/gkn653","article-title":"PID: the pathway interaction database","volume":"37","author":"Schaefer","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012511151615200_B37","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/nature08489","article-title":"Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution","volume":"461","author":"Shah","year":"2009","journal-title":"Nature"},{"key":"2023012511151615200_B38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1535-6108(02)00159-9","article-title":"Telomerase: a target for cancer therapeutics","volume":"2","author":"Shay","year":"2002","journal-title":"Cancer Cell"},{"key":"2023012511151615200_B39","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1126\/science.1133427","article-title":"The consensus coding sequences of human breast and colorectal cancers","volume":"314","author":"Sj\u00f6blom","year":"2006","journal-title":"Science"},{"key":"2023012511151615200_B40","volume-title":"Biometry","author":"Sokal","year":"1981","edition":"2"},{"key":"2023012511151615200_B41","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/ng1571","article-title":"A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer","volume":"37","author":"Stephens","year":"2005","journal-title":"Nat. Genet."},{"key":"2023012511151615200_B42","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/bioinformatics\/btn577","article-title":"A novel signaling pathway impact analysis","volume":"25","author":"Tarca","year":"2009","journal-title":"Bioinformatics"},{"key":"2023012511151615200_B43","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1007\/978-3-642-12683-3_33","article-title":"Algorithms for detecting significantly mutated pathways in cancer","volume":"6044","author":"Vandin","year":"2010","journal-title":"Lect. Notes Comput. Sci."},{"key":"2023012511151615200_B44","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nm1087","article-title":"Cancer genes and the pathways they control","volume":"10","author":"Vogelstein","year":"2004","journal-title":"Nat. Med."},{"key":"2023012511151615200_B45","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2307\/1905466","article-title":"Compounding probabilities from independent significance tests","volume":"10","author":"Wallis","year":"1942","journal-title":"Econometrica"},{"key":"2023012511151615200_B46","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1073\/pnas.261714699","article-title":"Prevalence of somatic alterations in the colorectal cancer cell genome","volume":"99","author":"Wang","year":"2002","journal-title":"Proc. Natl Acad. Sci."},{"key":"2023012511151615200_B47","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-6-245","article-title":"Extension of Lander\u2013Waterman theory for sequencing filtered DNA libraries","volume":"6","author":"Wendl","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"2023012511151615200_B48","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1126\/science.1145720","article-title":"The genomic landscapes of human breast and colorectal cancers","volume":"318","author":"Wood","year":"2007","journal-title":"Science"},{"key":"2023012511151615200_B49","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1109\/TNN.2005.845141","article-title":"Survey of clustering algorithms","volume":"16","author":"Xu","year":"2005","journal-title":"IEEE Trans. Neural Netw."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/12\/1595\/48864021\/bioinformatics_27_12_1595.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/12\/1595\/48864021\/bioinformatics_27_12_1595.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T11:21:53Z","timestamp":1674645713000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/27\/12\/1595\/256037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,4,14]]},"references-count":49,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2011,6,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btr193","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2011,6,15]]},"published":{"date-parts":[[2011,4,14]]}}}