New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.

Published

Journal Article

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). CONCLUSION: 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.

Full Text

Duke Authors

Cited Authors

  • Ross, JS; Wang, K; Gay, L; Al-Rohil, R; Rand, JV; Jones, DM; Lee, HJ; Sheehan, CE; Otto, GA; Palmer, G; Yelensky, R; Lipson, D; Morosini, D; Hawryluk, M; Catenacci, DVT; Miller, VA; Churi, C; Ali, S; Stephens, PJ

Published Date

  • March 2014

Published In

Volume / Issue

  • 19 / 3

Start / End Page

  • 235 - 242

PubMed ID

  • 24563076

Pubmed Central ID

  • 24563076

Electronic International Standard Serial Number (EISSN)

  • 1549-490X

Digital Object Identifier (DOI)

  • 10.1634/theoncologist.2013-0352

Language

  • eng

Conference Location

  • United States