Log in

Exploration of Potential Genomic Portraits Associated with Intrahepatic Recurrence in Human Hepatocellular Carcinoma

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

Abstract

Background

Hepatocellular carcinoma (HCC) is a heterogeneous disease with recognized variability in virus infection, genetic features, and clinical outcome. To date, transcriptional profilings of HCC have been used to predict recurrence or survival/prognosis. However, there remains a challenge to identify specific genomic prints associated with HCC recurrence, which could lead to novel therapies or effective treatment. Here we examine the association between biological signals and intrahepatic recurrence using global gene expression profiles and powerful analytical methods.

Materials and Methods

Gene expression profiles were generated in 24 HCC patients with hepatitis B infections (B-type HCC) and 60 HCC patients with hepatitis C infections (C-type HCC). Gene set enrichment analysis (GSEA) was applied to the entire ranked gene lists related to early intrahepatic recurrence, based on “ideal discriminator method.”

Results

GSEA revealed Ribosomal Proteins as a common regulatory pathway in B-type (P < .001) and C-type (P = .003) HCC recurrence. In addition, Proteasome (P < .001) and Pentose Phosphate Pathway (P = .01) were identified as specific pathways in each type of HCC recurrence, respectively.

Conclusions

Understanding these biologically common and different mechanisms related to intrahepatic recurrence in B-type and C-type HCC could be useful in the development of new therapeutic strategies in our fight against HCC.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–43.

    Article  CAS  PubMed  Google Scholar 

  2. Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 2000;89:500–7.

    Article  CAS  PubMed  Google Scholar 

  3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.

    Article  PubMed  Google Scholar 

  4. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.

    Article  CAS  PubMed  Google Scholar 

  5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  CAS  PubMed  Google Scholar 

  6. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  CAS  PubMed  Google Scholar 

  7. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003;33:49–54.

    Article  CAS  PubMed  Google Scholar 

  8. Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–7.

    Article  CAS  PubMed  Google Scholar 

  9. Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res. 2002;62:3939–44.

    CAS  PubMed  Google Scholar 

  10. Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.

    Article  CAS  PubMed  Google Scholar 

  12. Yoshioka S, Takemasa I, Nagano H, Kittaka N, Noda T, Wada H, et al. Molecular prediction of early recurrence after resection of hepatocellular carcinoma. Eur J Cancer. 2009;5:881–9.

    Article  Google Scholar 

  13. Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res. 2007;13:6275–83.

    Article  CAS  PubMed  Google Scholar 

  14. Woo HG, Park ES, Cheon JH, Kim JH, Lee JS, Park BJ, et al. Gene expression-based recurrence prediction of hepatitis B virus-related human hepatocellular carcinoma. Clin Cancer Res. 2008;14:2056–64.

    Article  CAS  PubMed  Google Scholar 

  15. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  Google Scholar 

  16. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005;105:1851–61.

    Article  CAS  PubMed  Google Scholar 

  17. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R. Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res. 2003;63:8312–7.

    CAS  PubMed  Google Scholar 

  18. Takeno A, Takemasa I, Doki Y, Yamasaki M, Miyata H, Takiguchi S, et al. Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer. 2008;99:1307–15.

    Article  CAS  PubMed  Google Scholar 

  19. Kittaka N, Takemasa I, Takeda Y, Marubashi S, Nagano H, Umeshita K, et al. Molecular map** of human hepatocellular carcinoma provides deeper biological insight from genomic data. Eur J Cancer. 2008;44:885–97.

    Article  CAS  PubMed  Google Scholar 

  20. Troyanskaya OG, Garber ME, Brown PO, Botstein D, Altman RB. Nonparametric methods for identifying differentially expressed genes in microarray data. Bioinformatics. 2002;18:1454–61.

    Article  CAS  PubMed  Google Scholar 

  21. Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530–6.

    Article  PubMed  Google Scholar 

  22. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–7.

    Article  CAS  PubMed  Google Scholar 

  23. Dahlquist KD, Salomonis N, Vranizan K, Lawlor SC, Conklin BR. GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways. Nat Genet. 2002;31:19–20.

    Article  CAS  PubMed  Google Scholar 

  24. Hu XT, Chen W, Wang D, Shi QL, Zhang FB, Liao YQ, et al. The proteasome subunit PSMA7 located on the 20q13 amplicon is overexpressed and associated with liver metastasis in colorectal cancer. Oncol Rep. 2008;19:441–6.

    CAS  PubMed  Google Scholar 

  25. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, et al. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer. 2006;94:578–85.

    Article  CAS  PubMed  Google Scholar 

  26. Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J, Weiss C, et al. Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int J Cancer. 2008;122:2422–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank Kenichi Matsubara, Ph.D. (President and Executive Director of The DNA Chip Research Inc., Yokohama Japan) for contract services on AceGene Human 30K.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ichiro Takemasa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 7423 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kittaka, N., Takemasa, I., Seno, S. et al. Exploration of Potential Genomic Portraits Associated with Intrahepatic Recurrence in Human Hepatocellular Carcinoma. Ann Surg Oncol 17, 3145–3154 (2010). https://doi.org/10.1245/s10434-010-1150-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-010-1150-9

Keywords

Navigation