Gastroenterology

Gastroenterology

Volume 142, Issue 4, April 2012, Pages 1021-1031.e15
Gastroenterology

Original Research
Basic and Translational—Biliary
Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors

https://doi.org/10.1053/j.gastro.2011.12.005Get rights and content

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 (SGI–IV; 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.

Section snippets

Materials and Methods

Detailed information is provided in Supplementary Materials and Methods.

Transcriptomic Profiling Identifies 2 Distinct CCA Subclasses With Different Clinical Outcomes

The molecular profiles of the resected tumors were readily distinguishable from a group of matched noncancerous surrounding livers (Supplementary Figure 1A). This classification was confirmed by Bayesian compound covariate prediction modeling with 97% accuracy (95% confidence interval [CI], 0.93−0.99; P < .0001) (Supplementary Figure 1B). Within the cohort, the resected tumors of hilar (36/104) and peripheral type (68/104) were not distinguishable by anatomic location based on overall survival (

Discussion

We performed a comprehensive molecular and genomic characterization of 104 surgically resected CCAs. Our 238-gene classifier identified a high-risk group of patients with CCA, significantly differentiating patients according to overall and recurrence-free survival independent of specific clinical subtypes. Reflecting the strength of the classifier, it could be further reduced to 36 genes, which differentiated individuals in outcome-linked categories with greater accuracy. A comparison with our

Acknowledgments

The authors thank Tanya Hoang (Laboratory of Experimental Carcinogenesis, National Cancer Institute) for laboratory assistance and Teresa Mettler (Mayo Clinic) for abstracting clinical data.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health grants CA100882 and CA128633 (to L.R.R.) and P30DK084567 (Mayo Clinic Center for Cell Signaling in Gastroenterology); and grant 271-070712 from the Danish Medical Research Council (to J.B.A.).

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