ABSTRACT
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
Subject(s)
Databases, Genetic , Neoplasms/pathology , Signal Transduction/genetics , Genes, Neoplasm , Humans , Neoplasms/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Wnt Proteins/genetics , Wnt Proteins/metabolismABSTRACT
MOTIVATION: While existing network visualization tools enable the exploration of cancer genomics data, most biologists prefer simplified, curated pathway diagrams, such as those featured in many manuscripts from The Cancer Genome Atlas (TCGA). These pathway diagrams typically summarize how a pathway is altered in individual cancer types, including alteration frequencies for each gene. RESULTS: To address this need, we developed the web-based tool PathwayMapper, which runs in most common web browsers. It can be used for viewing pre-curated cancer pathways, or as a graphical editor for creating new pathways, with the ability to overlay genomic alteration data from cBioPortal. In addition, a collaborative mode is available that allows scientists to co-operate interactively on constructing pathways, with support for concurrent modifications and built-in conflict resolution. AVAILABILITY AND IMPLEMENTATION: The PathwayMapper tool is accessible at http://pathwaymapper.org and the code is available on Github ( https://github.com/iVis-at-Bilkent/pathway-mapper ). CONTACT: ivis@cs.bilkent.edu.tr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
