title: New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.
abstract: BACKGROUND
  Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy.
  
  
  METHODS
  DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 μm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage.
  
  
  RESULTS
  The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1).
  
  
  CONCLUSIONS
  Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA; Foundation Medicine, Inc., Cambridge, Massachusetts, USA; University of Chicago, Chicago, Illinois, USA; The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Laurie
authors.initials: L
authors.lastname: Gay
authors.forename: Rami
authors.initials: R
authors.lastname: Al-Rohil
authors.forename: Janne V
authors.initials: JV
authors.lastname: Rand
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.forename: Hwa J
authors.initials: HJ
authors.lastname: Lee
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Otto
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.forename: Matthew
authors.initials: M
authors.lastname: Hawryluk
authors.forename: Daniel V T
authors.initials: DV
authors.lastname: Catenacci
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Churi
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
keywords: Driver mutations; Intrahepatic cholangiocarcinoma; Next-generation sequencing; Targeted therapy