Journal Article

Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Zinner, Ralph, Hong, David, Zuo, Mingxin, Wolff, Robert A., Wang, Ying, Kang, HyunSeon C., Mills, Gordon, Javle, Milind, Mishra, Lopa, Crane, Christopher H., Shroff, Rachna, Meric-Bernstam, Funda, Janku, Filip, Churi, Chaitanya R., Weatherly, Jacqueline, Rashid, Asif, Vauthey, Jean-Nicholas

2014

Overview

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. 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. 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. There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Adult / Aged / Aged, 80 and over / Bile Ducts, Intrahepatic - pathology / Biliary tract cancer / Biology and Life Sciences / Cancer / Cancer genetics / Cancer therapies / Cdc4 protein / Chemotherapy / Cholangiocarcinoma / Cholangiocarcinoma - genetics / Cholangiocarcinoma - pathology / Cholangiocarcinoma - therapy / Chromatin / Clinical trials / Dehydrogenases / Demography / Deoxyribonucleic acid / Disease-Free Survival / DNA / DNA Mutational Analysis / DNA repair / Epidermal growth factor receptors / ErbB-2 protein / Exons / Female / Fibroblast growth factor receptors / Gallbladder / Gene amplification / Gene sequencing / Genes / Genes, Neoplasm - genetics / Genetic aspects / Genome, Human - genetics / Health aspects / Humans / Identification methods / Introns / K-Ras protein / Liver cancer / Lung cancer / Male / MAP kinase / Mcl-1 protein / Medical prognosis / Medical records / Medical research / Medicine and Health Sciences / MEK inhibitors / Metastases / Middle Aged / Molecular Targeted Therapy / Multivariate Analysis / Mutation / Mutation - genetics / Oncogene Proteins, Fusion - genetics / Opisthorchis viverrini / p53 Protein / Patients / Profiling / Prognosis / Raf protein / Receptors, Fibroblast Growth Factor - genetics / Regression Analysis / Research and analysis methods / Review boards / Signal Transduction - genetics / Smad4 protein / Subgroups / TOR protein / Treatment Outcome / Tumor proteins / Tumor Suppressor Protein p53 - genetics / Young Adult