Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors

TY - JOUR

T1 - Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors

AU - Andersen, Jesper Bøje

AU - Spee, Bart

AU - Blechacz, Boris R

AU - Avital, Itzhak

AU - Komuta, Mina

AU - Barbour, Andrew

AU - Conner, Elizabeth A

AU - Gillen, Matthew C

AU - Roskams, Tania

AU - Roberts, Lewis R

AU - Factor, Valentina M

AU - Thorgeirsson, Snorri S

N1 - Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2012/4

Y1 - 2012/4

N2 - Background & Aims: Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. Methods: We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. Results: Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ2 = 11.61; P <.0007), time to recurrence (13.7 vs 22.7 months; P <.001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGIIV; χ2 = 8.34; P <.03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. Conclusions: We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.

AB - Background & Aims: Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. Methods: We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. Results: Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ2 = 11.61; P <.0007), time to recurrence (13.7 vs 22.7 months; P <.001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGIIV; χ2 = 8.34; P <.03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. Conclusions: We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.

KW - Aged

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Agents

KW - Belgium

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Blotting, Western

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Chi-Square Distribution

KW - Cholangiocarcinoma

KW - Cluster Analysis

KW - Female

KW - Gene Expression Profiling

KW - Genetic Predisposition to Disease

KW - Humans

KW - Immunohistochemistry

KW - Individualized Medicine

KW - Kaplan-Meier Estimate

KW - Laser Capture Microdissection

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Mutation

KW - Oligonucleotide Array Sequence Analysis

KW - Patient Selection

KW - Phenotype

KW - Prognosis

KW - Proportional Hazards Models

KW - Protein Kinase Inhibitors

KW - Protein-Tyrosine Kinases

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins B-raf

KW - Queensland

KW - Quinazolines

KW - Receptor, Epidermal Growth Factor

KW - Risk Assessment

KW - Risk Factors

KW - Survival Rate

KW - Time Factors

KW - Tumor Microenvironment

KW - United States

KW - ras Proteins

U2 - 10.1053/j.gastro.2011.12.005

DO - 10.1053/j.gastro.2011.12.005

M3 - Journal article

C2 - 22178589

SN - 0016-5085

VL - 142

SP - 1021-1031.e15

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -