Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Annals of Surgical Oncology (Impact Factor: 3.93). 06/2014; 21(12). DOI: 10.1245/s10434-014-3828-x
Source: PubMed



The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.


Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.


The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cholangiocarcinoma is a heterogeneous malignant process, which is further classified into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The poor prognosis of the disease is partly due to the lack of understanding of the disease mechanism. Multiple gene alterations identified by various molecular techniques have been described recently. As a result, multiple targeted therapies for ICC and ECC are being developed. In this study, we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing (NGS) (Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips). Eleven of 16 samples passed internal quality control established for NGS testing. ICC cases (n=3) showed IDH1 (33.3%) and NRAS (33.3%) mutations. Meanwhile, TP53 (75%), KRAS (50%), and BRAF (12.5%) mutations were identified in ECC cases (n=8). Our study confirmed the molecular heterogeneity of ICC and ECC using NGS. This information will be important for individual patients as targeted therapies for ICC and ECC become available in the future. Copyright © 2015. Published by Elsevier Inc.
    No preview · Conference Paper · Nov 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are common primary liver cancers worldwide. However, the survival and prognosis of ICC are much poorer than those of HCC, indicating the different molecular characteristics and mechanisms between ICC and HCC. To identify differentially expressed (DE) genes between ICC and HCC or combined hepatocellular-cholangiocarcinoma (CHC), we performed integrated analysis of publicly available microarray Gene Expression Omnibus (GEO) datasets by MetaOmics. Three GEO datasets comprising 32 ICC biochips, 77 HCC biochips, and 34 CHC biochips were available for the data integration. We identified 7313 DE genes between ICC and HCC, including 3650 upregulated genes and 3663 downregulated genes. The S100 family members on chromosome 1q21 were extensively upregulated in ICC, and S100A11 had the greatest degree of upregulation in ICC. Based on the DE genes, combined gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed the enhanced pathways of local adhesion, ECM-receptor interaction, and regulation of action cytoskeleton, suggesting the enhanced communication between ICC and the microenvironment. Additionally, development-related genes and development-related pathways, including the Notch, Wnt, and TGF-β signaling pathways, were shown to be active prominently in ICC. Taken together, we identified the characteristically upregulated or downregulated DE genes and pathways in ICC compared with HCC or CHC. These DE genes and pathways supply new transcriptomics evidence for ICC and could help identify new therapeutic targets.
    No preview · Article · Feb 2015 · Tumor Biology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The benefit of chemotherapy for surgically resected intrahepatic cholangiocarcinoma (ICC) remains poorly defined. The present study sought to determine the survival impact of chemotherapy for surgically resected ICC. Patients with non-metastatic ICC who underwent surgery were identified from the National Cancer Database (1998-2011) and stratified by receipt of chemotherapy. Survival outcomes were analyzed following propensity score modeling using the greedy matching algorithm. A total of 2751 patients were identified (median age 64 years); 985 (35.8 %) received chemotherapy. Younger age, advanced tumor stage, R1/R2 surgical margins, and lymph node metastasis were all independently associated with receipt of chemotherapy (p < 0.05). Following propensity score matching, advanced tumor stage, lymph node metastasis, poorly differentiated tumors, and R1/R2 surgical margins were associated with poorer overall survival (OS) (p < 0.05). Median OS comparing patients who received chemotherapy compared with surgery alone was 23 versus 20 months (p = 0.09). However, when stratified by lymph node status, chemotherapy demonstrated a significant improvement in median OS among N1 patients (19.8 vs. 10.7 months; p < 0.001). In contrast, patients with N0 disease derived no benefit from chemotherapy (29.4 vs. 29 months; p = 0.33). Additional tumor characteristics associated with improved survival with chemotherapy included T3/T4 tumors (21.3 vs. 15.6 months; p < 0.001) and R1/R2 surgical margins (19.5 vs. 11.6 months; p = 0.006). The use of chemotherapy was associated with a survival benefit only for ICC patients with nodal metastasis, advanced tumor stage, or an inadequate surgical resection. Chemotherapy for resected ICC should be strongly considered for tumors harboring high-risk features.
    No preview · Article · Mar 2015 · Annals of Surgical Oncology
Show more