title: An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types.
abstract: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers.
  
  
  
  We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal.
  
  
  
  The code is available at: http://www.taehyunlab.org
  
  
  
  jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com
  
  
  
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sunho
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Computer Science and Electrical Engineering, University of Maryland at Baltimore County, Baltimore, MD, USA.
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Statistics, Keimyung University, Daegu, South Korea.
authors.forename: Donghyeon
authors.initials: D
authors.lastname: Yu
authors.affiliation: Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.affiliation: Center for Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jianjiong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jin Suk
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Norris
authors.affiliation: Department of Statistical Science, Southern Methodist University, Dallas, TX, USA.
authors.forename: Xinlei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Mathematical Sciences, University of Texas at Dallas, Dallas, TX, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Obstetrics, Gynecology & Women's Health, University of Minnesota Twin Cities, Minneapolis, MN, USA.
authors.forename: Jeongsik
authors.initials: J
authors.lastname: Yong
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zabi
authors.initials: Z
authors.lastname: Wardak
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Choe
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Story
authors.affiliation: Genetics, Cell Biology, University of Minnesota Twin Cities, Minneapolis, MN, USA, Masonic Cancer Center, University of Minnesota Twin Cities, Minneapolis, MN, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Starr
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea and Open NBI Convergence Technology Research Laboratory, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cheong
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Hwang
mesh_terms: D004252:DNA Mutational Analysis; D053263:Gene Regulatory Networks; D023281:Genomics; D006801:Humans; D009154:Mutation; D009369:Neoplasms