PMID- 22178589 OWN - NLM STAT- MEDLINE DCOM- 20120531 LR - 20240513 IS - 1528-0012 (Electronic) IS - 0016-5085 (Print) IS - 0016-5085 (Linking) VI - 142 IP - 4 DP - 2012 Apr TI - Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. PG - 1021-1031.e15 LID - 10.1053/j.gastro.2011.12.005 [doi] 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%; chi(2) = 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 (SGI-IV; chi(2) = 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. CI - Copyright (c) 2012 AGA Institute. Published by Elsevier Inc. All rights reserved. FAU - Andersen, Jesper B AU - Andersen JB AD - Laboratory of Experimental Carcinogenesis, National Institutes of Health, Bethesda, Maryland 20892-4262, USA. FAU - Spee, Bart AU - Spee B FAU - Blechacz, Boris R AU - Blechacz BR FAU - Avital, Itzhak AU - Avital I FAU - Komuta, Mina AU - Komuta M FAU - Barbour, Andrew AU - Barbour A FAU - Conner, Elizabeth A AU - Conner EA FAU - Gillen, Matthew C AU - Gillen MC FAU - Roskams, Tania AU - Roskams T FAU - Roberts, Lewis R AU - Roberts LR FAU - Factor, Valentina M AU - Factor VM FAU - Thorgeirsson, Snorri S AU - Thorgeirsson SS LA - eng GR - R01 CA100882/CA/NCI NIH HHS/United States GR - P30DK084567/DK/NIDDK NIH HHS/United States GR - ZIA BC011173-03/ImNIH/Intramural NIH HHS/United States GR - P30 DK084567/DK/NIDDK NIH HHS/United States GR - CA128633/CA/NCI NIH HHS/United States GR - R56 CA100882/CA/NCI NIH HHS/United States GR - R21 CA128633/CA/NCI NIH HHS/United States GR - CA100882/CA/NCI NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20111213 PL - United States TA - Gastroenterology JT - Gastroenterology JID - 0374630 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (KRAS protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Quinazolines) RN - 0VUA21238F (Lapatinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - EC 3.6.5.2 (ras Proteins) RN - P188ANX8CK (Trastuzumab) SB - IM CIN - Gastroenterology. 2012 Oct;143(4):e20-1; author reply e21. doi: 10.1053/j.gastro.2012.07.120. PMID: 22921673 MH - Aged MH - Antibodies, Monoclonal, Humanized/pharmacology MH - Antineoplastic Agents/*pharmacology MH - Belgium MH - Bile Duct Neoplasms/drug therapy/enzymology/*genetics/mortality/pathology MH - *Bile Ducts, Intrahepatic/enzymology/pathology MH - Blotting, Western MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Chi-Square Distribution MH - Cholangiocarcinoma/drug therapy/enzymology/*genetics/mortality/pathology MH - Cluster Analysis MH - ErbB Receptors/antagonists & inhibitors/genetics MH - Female MH - Gene Expression Profiling/methods MH - Genetic Predisposition to Disease MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - Lapatinib MH - Laser Capture Microdissection MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - Mutation MH - Oligonucleotide Array Sequence Analysis MH - Patient Selection MH - Phenotype MH - Precision Medicine MH - Prognosis MH - Proportional Hazards Models MH - Protein Kinase Inhibitors/*pharmacology MH - Protein-Tyrosine Kinases/analysis/*antagonists & inhibitors/*genetics MH - Proto-Oncogene Proteins/antagonists & inhibitors/genetics MH - Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics MH - Proto-Oncogene Proteins p21(ras) MH - Queensland MH - Quinazolines/pharmacology MH - Risk Assessment MH - Risk Factors MH - Survival Rate MH - Time Factors MH - Trastuzumab MH - Tumor Microenvironment MH - United States MH - ras Proteins/antagonists & inhibitors/genetics PMC - PMC3413201 MID - NIHMS344101 COIS- Conflicts of interest The authors disclose no conflicts. EDAT- 2011/12/20 06:00 MHDA- 2012/06/01 06:00 PMCR- 2013/04/01 CRDT- 2011/12/20 06:00 PHST- 2011/07/25 00:00 [received] PHST- 2011/11/14 00:00 [revised] PHST- 2011/12/01 00:00 [accepted] PHST- 2011/12/20 06:00 [entrez] PHST- 2011/12/20 06:00 [pubmed] PHST- 2012/06/01 06:00 [medline] PHST- 2013/04/01 00:00 [pmc-release] AID - S0016-5085(11)01662-3 [pii] AID - 10.1053/j.gastro.2011.12.005 [doi] PST - ppublish SO - Gastroenterology. 2012 Apr;142(4):1021-1031.e15. doi: 10.1053/j.gastro.2011.12.005. Epub 2011 Dec 13.