Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Chaitanya Churi(The University of Texas MD Anderson Cancer Center), Rachna T. Shroff(The University of Texas MD Anderson Cancer Center), Ying Wang(The University of Texas MD Anderson Cancer Center), Asif Rashid(The University of Texas MD Anderson Cancer Center), Hyunseon C. Kang(The University of Texas MD Anderson Cancer Center), J. Weatherly(The University of Texas MD Anderson Cancer Center), Mingxin Zuo(The University of Texas MD Anderson Cancer Center), Ralph Zinner(The University of Texas MD Anderson Cancer Center), David S. Hong(The University of Texas MD Anderson Cancer Center), Funda Meric‐Bernstam(The University of Texas MD Anderson Cancer Center), Filip Jankú(The University of Texas MD Anderson Cancer Center), Christopher H. Crane(The University of Texas MD Anderson Cancer Center), Lopa Mishra(The University of Texas MD Anderson Cancer Center), J.N. Vauthey(The University of Texas MD Anderson Cancer Center), Robert A. Wolff(The University of Texas MD Anderson Cancer Center), Gordon B. Mills(The University of Texas MD Anderson Cancer Center), Milind Javle(The University of Texas MD Anderson Cancer Center)
PLoS ONE
December 23, 2014
10.1371/journal.pone.0115383
Cited by 454Open Access
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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. CONCLUSION: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

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