Skip to main content

Advertisement

SpringerLink
Log in

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

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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 < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40:472–7.

    Article  PubMed  Google Scholar 

  2. Poultsides GA, Zhu AX, Choti MA, et al. Intrahepatic cholangiocarcinoma. Surg Clin North Am. 2010;90:817–37.

    Article  PubMed  Google Scholar 

  3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.

    Article  PubMed  CAS  Google Scholar 

  4. Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–40.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Sia D, Tovar V, Moeini A, et al. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013;32:4861–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17:72–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Tannapfel A, Sommerer F, Benicke M, et al. Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J Pathol. 2002;197:624–31.

    Article  PubMed  CAS  Google Scholar 

  8. Voss JS, Holtegaard LM, Kerr SE, et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol. 2013;44:1216–22.

    Article  PubMed  CAS  Google Scholar 

  9. Xu RF, Sun JP, Zhang SR, et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother. 2011;65:22–6.

    Article  PubMed  CAS  Google Scholar 

  10. Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45:1470–3.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32:3091–100.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142:1021–31.e15.

    Article  Google Scholar 

  13. Dias-Santagata D, Akhavanfard S, David SS, et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med. 2010;2:146–58.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer. 2013;119:4137–44.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Bazan V, Agnese V, Corsale S, et al. Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell’Italia Meridionale (GOIM) prospective study. Ann Oncol. 2005;16(Suppl 4):iv50–5.

  16. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the “RASCAL II” study. Br J Cancer. 2001;85:692–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Woo HG, Park ES, Thorgeirsson SS, et al. Exploring genomic profiles of hepatocellular carcinoma. Mol Carcinog. 2011;50:235–43.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Lee S, Lee HJ, Kim JH, et al. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Minguez B, Tovar V, Chiang D, et al. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol. 2009;25:186–94.

    Article  PubMed  CAS  Google Scholar 

  20. Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008;10:77–82.

    Article  CAS  Google Scholar 

  21. Robertson S, Hyder O, Dodson R, et al. The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome. Hum Pathol. 2013;44:2768–73.

    Article  PubMed  CAS  Google Scholar 

  22. Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut. 2000;47:721–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144:829–40.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.

    Article  PubMed  CAS  Google Scholar 

  28. Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43:1552–8.

    Article  PubMed  CAS  Google Scholar 

  29. Chan-On W, Nairismagi ML, Ong CK, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–8.

    Article  PubMed  CAS  Google Scholar 

  30. Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat Genet. 2012;44:690–3.

    Article  PubMed  CAS  Google Scholar 

  31. Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636–47.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012;28:266–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Riener MO, Bawohl M, Clavien PA, et al. Rare PIK3CA hotspot mutations in carcinomas of the biliary tract. Genes Chromosomes Cancer. 2008;47:363–7.

    Article  PubMed  CAS  Google Scholar 

  34. Ross JS, Wang J, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinoma revealed by next-generation sequencing. Oncologist. 2014;19:235–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgment

We thank Kenneth C. Fan, Hector U. Lopez, and Christina R. Matulis for their technical assistance and Daniel J. Harris for data collection. Supported in part by Agios.

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Andrew X. Zhu MD, Darrell R. Borger MD, Vikram Deshpande MD & Cristina Ferrone MD

  2. Johns Hopkins University, Baltimore, MD, USA

    Yuhree Kim MD, David Cosgrove MD, Aslam Ejaz MD, Robert A. Anders MD & Timothy M. Pawlik MD, MPH, PhD

  3. Fundeni Clinical Institute of Digestive Diseases and Liver Transplantation, Bucharest, Romania

    Sorin Alexandrescu MD & Irinel Popescu MD

  4. Medical College of Wisconsin, Milwaukee, WI, USA

    Ryan Thomas Groeschl MD & T. Clark Gamblin MD

  5. University of Virginia, Charlottesville, VA, USA

    James M. Lindberg MD & Todd W. Bauer MD

  6. Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Christine Sempoux MD & Jean Francois Gigot MD

  7. The University of Hong Kong, Hong Kong, Hong Kong

    Thomas Yau MD & Ronnie Poon MD

Authors
  1. Andrew X. Zhu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darrell R. Borger MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuhree Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Cosgrove MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aslam Ejaz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sorin Alexandrescu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryan Thomas Groeschl MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vikram Deshpande MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James M. Lindberg MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cristina Ferrone MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christine Sempoux MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Thomas Yau MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ronnie Poon MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Irinel Popescu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Todd W. Bauer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. T. Clark Gamblin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jean Francois Gigot MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Robert A. Anders MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Timothy M. Pawlik MD, MPH, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy M. Pawlik MD, MPH, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 46 kb)

Supplementary material 2 (DOCX 32 kb)

Supplementary material 3 (TIFF 1521 kb)

Supplementary material 4 (TIFF 1521 kb)

Supplementary material 5 (TIFF 1521 kb)

Supplementary Fig. 1

Overall survival stratified by a no identified mutation versus “any” mutation cases b no identified mutation vs. KRAS or BRAF mutant cases c noidentified mutation versuss PIK3CA or PTEN mutant cases d no identified mutation versus IDH1 or IDH. Supplementary material 6 (TIFF 1521 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, A.X., Borger, D.R., Kim, Y. et al. Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets. Ann Surg Oncol 21, 3827–3834 (2014). https://doi.org/10.1245/s10434-014-3828-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-014-3828-x

Keywords

Search

Navigation