Oncogenic Signaling Pathways in The Cancer Genome Atlas


Francisco Sanchez-Vega, Memorial Sloan-Kettering Cancer Center
Marco Mina, Université de Lausanne (UNIL)
Joshua Armenia, Memorial Sloan-Kettering Cancer Center
Walid K. Chatila, Memorial Sloan-Kettering Cancer Center
Augustin Luna, Dana-Farber Cancer Institute
Konnor C. La, Memorial Sloan-Kettering Cancer Center
Sofia Dimitriadoy, Princeton University
David L. Liu, Dana-Farber Cancer Institute
Havish S. Kantheti, The University of Texas at Dallas
Sadegh Saghafinia, Université de Lausanne (UNIL)
Debyani Chakravarty, Memorial Sloan-Kettering Cancer Center
Foysal Daian, Memorial Sloan-Kettering Cancer Center
Qingsong Gao, Washington University School of Medicine in St. Louis
Matthew H. Bailey, Washington University School of Medicine in St. Louis
Wen Wei Liang, Washington University School of Medicine in St. Louis
Steven M. Foltz, Washington University School of Medicine in St. Louis
Ilya Shmulevich, Institute for Systems Biology
Li Ding, Washington University School of Medicine in St. Louis
Zachary Heins, Memorial Sloan-Kettering Cancer Center
Angelica Ochoa, Memorial Sloan-Kettering Cancer Center
Benjamin Gross, Memorial Sloan-Kettering Cancer Center
Jianjiong Gao, Memorial Sloan-Kettering Cancer Center
Hongxin Zhang, Memorial Sloan-Kettering Cancer Center
Ritika Kundra, Memorial Sloan-Kettering Cancer Center
Cyriac Kandoth, Memorial Sloan-Kettering Cancer Center
Istemi Bahceci, Bilkent Üniversitesi
Leonard Dervishi, Bilkent Üniversitesi
Ugur Dogrusoz, Bilkent Üniversitesi
Wanding Zhou, Van Andel Research Institute
Hui Shen, Van Andel Research Institute
Peter W. Laird, Van Andel Research Institute
Gregory P. Way, University of Pennsylvania
Casey S. Greene, University of Pennsylvania

Document Type

Journal Article

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cancer genome atlas; cancer genomics; combination therapy; pan-cancer; PanCanAtlas; precision oncology; signaling pathways; TCGA; therapeutics; whole exome sequencing


© 2018 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, TGFβ signaling, p53 and β-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. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

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