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. 2018 Sep 1;24(17):4154-4161.
doi: 10.1158/1078-0432.CCR-18-0078. Epub 2018 May 30.

Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention

Maeve A Lowery  1 , Ryan Ptashkin  2 , Emmet Jordan  2 , Michael F Berger  2 , Ahmet Zehir  2 , Marinela Capanu  2 , Nancy E Kemeny  2   3 , Eileen M O'Reilly  2   3 , Imane El-Dika  2 , William R Jarnagin  2   3 , James J Harding  2   3 , Michael I D'Angelica  2   3 , Andrea Cercek  2   3 , Jaclyn F Hechtman  2 , David B Solit  2   3 , Nikolaus Schultz  2 , David M Hyman  2   3 , David S Klimstra  2   3 , Leonard B Saltz  2   3 , Ghassan K Abou-Alfa  4   3
Affiliations

Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention

Maeve A Lowery et al. Clin Cancer Res. .

Abstract

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2 Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154-61. ©2018 AACR.

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Conflict of interest statement

Potential conflicts of interest: None for all authors

Figures

Figure 1.
Figure 1.. Common mutations and OncoKB annotation.
KRAS, SMAD4 and STK11alterations were more commonly seen in extrahepatic cholangiocarcinoma, whereas mutations in IDH1, BAP1, TP53 and FGFR2 fusions occurred with greater frequency in intrahepatic cases
Figure 2:
Figure 2:. FGFR2 gene fusions.
Multiple fusion partners with FGFR2 were identified, the most frequent being BICC1 and KIAA1217
Figure 3:
Figure 3:. Progression free survival on 1st line chemotherapy for advanced disease.
Patients with alterations in CDKN2A/B, ERBB2, and MDM2 had significantly shorter time to progression on first line chemotherapy.
See this image and copyright information in PMC

References

    1. Kim YMD, Zhang XF, Bagante F, Spolverato G, Schmidt C, Dilhoff M, Pawlik TM.: Evaluation of the 8th edition American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: A surveillance, epidemiology, and end results (SEER) analysis. J Surg Oncol. 2017. June 12. doi: 10.1002/jso.24720. - DOI - PubMed
    1. Razumilava N, Gores GJ: Cholangiocarcinoma. The Lancet 383:2168–2179 - PMC - PubMed
    1. Churi CR, Shroff R, Wang Y, et al.: Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications. PLoS ONE 9:e115383, 2014 - PMC - PubMed
    1. Jiao Y, Pawlik TM, Anders RA, et al.: Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45:1470–1473, 2013 - PMC - PubMed
    1. Andersen JB, Spee B, Blechacz BR, et al.: Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors. Gastroenterology 142:1021–1031. e15, 2012 - PMC - PubMed

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