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Annals of Surgical Oncology

, Volume 21, Issue 12, pp 3827–3834 | Cite as

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

  • Andrew X. Zhu
  • Darrell R. Borger
  • Yuhree Kim
  • David Cosgrove
  • Aslam Ejaz
  • Sorin Alexandrescu
  • Ryan Thomas Groeschl
  • Vikram Deshpande
  • James M. Lindberg
  • Cristina Ferrone
  • Christine Sempoux
  • Thomas Yau
  • Ronnie Poon
  • Irinel Popescu
  • Todd W. Bauer
  • T. Clark Gamblin
  • Jean Francois Gigot
  • Robert A. Anders
  • Timothy M. Pawlik
Hepatobiliary Tumors

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.

Keywords

Cholangiocarcinoma KRAS Mutation BRAF Mutation Vemurafenib IDH2 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

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Supplementary material 1 (DOCX 46 kb)
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Supplementary material 2 (DOCX 32 kb)
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Supplementary material 3 (TIFF 1521 kb)
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Supplementary material 4 (TIFF 1521 kb)
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Supplementary material 5 (TIFF 1521 kb)
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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)

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Poultsides GA, Zhu AX, Choti MA, et al. Intrahepatic cholangiocarcinoma. Surg Clin North Am. 2010;90:817–37.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–40.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Sia D, Tovar V, Moeini A, et al. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013;32:4861–70.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 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.Google Scholar
  16. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Woo HG, Park ES, Thorgeirsson SS, et al. Exploring genomic profiles of hepatocellular carcinoma. Mol Carcinog. 2011;50:235–43.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Lee S, Lee HJ, Kim JH, et al. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Minguez B, Tovar V, Chiang D, et al. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol. 2009;25:186–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008;10:77–82.CrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 28.
    Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43:1552–8.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat Genet. 2012;44:690–3.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012;28:266–72.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Andrew X. Zhu
    • 1
  • Darrell R. Borger
    • 1
  • Yuhree Kim
    • 2
  • David Cosgrove
    • 2
  • Aslam Ejaz
    • 2
  • Sorin Alexandrescu
    • 3
  • Ryan Thomas Groeschl
    • 4
  • Vikram Deshpande
    • 1
  • James M. Lindberg
    • 5
  • Cristina Ferrone
    • 1
  • Christine Sempoux
    • 6
  • Thomas Yau
    • 7
  • Ronnie Poon
    • 7
  • Irinel Popescu
    • 3
  • Todd W. Bauer
    • 5
  • T. Clark Gamblin
    • 4
  • Jean Francois Gigot
    • 6
  • Robert A. Anders
    • 2
  • Timothy M. Pawlik
    • 2
  1. 1.Massachusetts General Hospital Cancer CenterHarvard Medical SchoolBostonUSA
  2. 2.Johns Hopkins UniversityBaltimoreUSA
  3. 3.Fundeni Clinical Institute of Digestive Diseases and Liver TransplantationBucharestRomania
  4. 4.Medical College of WisconsinMilwaukeeUSA
  5. 5.University of VirginiaCharlottesvilleUSA
  6. 6.Cliniques Universitaires Saint-LucBrusselsBelgium
  7. 7.The University of Hong KongHong KongHong Kong

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