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Hepatology International

, Volume 13, Issue 4, pp 490–500 | Cite as

Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular–clinical analysis and potential targeted approach

  • Keun Soo Ahn
  • Daniel O’Brien
  • Yu Na Kang
  • Taofic Mounajjed
  • Yong Hoon Kim
  • Tae-Seok Kim
  • Jean-Pierre A. Kocher
  • Loretta K. Allotey
  • Mitesh J. BoradEmail author
  • Lewis R. RobertsEmail author
  • Koo Jeong KangEmail author
Original Article
  • 174 Downloads

Abstract

Background

Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes.

Methods

We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation.

Results

Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine.

Conclusions

Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment.

Keywords

Cholangiocarcinoma RNA sequence Gene expression Pathway Mutation KRAS Target therapy 

Notes

Acknowledgements

The authors thank Li Li, Dehai Wu, Katsuyuki Miyabe, Tao Song, Ning Zhang, Jianbo Huang, Shaoqing Wang, Lin Yang, and Amy S Mauer (Mayo clinic, Rochester, MN) for their help in the experiment. The biospecimens and data used for this study were provided by the Biobank of Keimyung University Dongsan Medical Center, member of the Korea Biobank Network. This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) (No. 2018R1C1B3004435). This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MSIP) (No. 2014R1A5A2010008).

Compliance with ethical standards

Conflict of interest

Keun Soo Ahn, Daniel O’Brien, Yu Na Kang, Taofic Mounajjed4, Yong Hoon Kim, Tae-Seok Kim, Jean-Pierre A. Kocher, Loretta K. Allotey, Mitesh J. Borad, Lewis R. Roberts, and Koo Jeong Kang declare that they have no conflict of interest.

Availability of data and materials

RNA sequencing data of this manuscript is registered at Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) with GEO accession number of GSE107943

Ethics approval

This study was approved by institutional review boards at both institutions (Keimyung University Dongsan Medical Center: IRB No. 2014-12-066, Mayo clinic: IRB No. 16-007369) and included secondary use of human-derived materials.

Informed consent

Informed consent for the human-derived materials was obtained from all patients before surgery.

Supplementary material

12072_2019_9954_MOESM1_ESM.xlsx (213 kb)
Supplementary material 1 (XLSX 212 kb)
12072_2019_9954_MOESM2_ESM.pdf (1 mb)
Supplementary material 2 (PDF 1035 kb)

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Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  1. 1.Department of Surgery, Dongsan Medical Center, School of MedicineKeimyung UniversityDaeguRepublic of Korea
  2. 2.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  3. 3.Department of Pathology, Dongsan Medical CenterKeimyung UniversityDaeguRepublic of Korea
  4. 4.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  5. 5.Department of Gastroenterology and HepatologyMayo ClinicRochesterUSA
  6. 6.University of Minnesota Medical SchoolMinneapolisUSA
  7. 7.Division of Hematology and Medical OncologyMayo ClinicScottsdaleUSA

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