title: Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
abstract: BACKGROUND
  Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.
  
  
  METHODS
  We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.
  
  
  RESULTS
  There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.
  
  
  CONCLUSIONS
  There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Churi
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Rachna
authors.initials: R
authors.lastname: Shroff
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: HyunSeon C
authors.initials: HC
authors.lastname: Kang
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Weatherly
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Zuo
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Crane
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jean-Nicholas
authors.initials: JN
authors.lastname: Vauthey
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gordon
authors.initials: G
authors.lastname: Mills
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Milind
authors.initials: M
authors.lastname: Javle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D004252:DNA Mutational Analysis; D003710:Demography; D018572:Disease-Free Survival; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D012044:Regression Analysis; D015398:Signal Transduction / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D015514:Oncogene Proteins, Fusion; D017468:Receptors, Fibroblast Growth Factor; D016159:Tumor Suppressor Protein p53