Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays

Oncogene volume 27, pages 6607–6622 (2008)Cite this article

Abstract

Propensity for subsequent distant metastasis in head and neck squamous-cell carcinoma (HNSCC) was analysed using 186 primary tumours from patients initially treated by surgery that developed (M) or did not develop (NM) metastases as the first recurrent event. Transcriptome (Affymetrix HGU133_Plus2, QRT–PCR) and array-comparative genomic hybridization data were collected. Non-supervised hierarchical clustering based on Affymetrix data distinguished tumours differing in pathological differentiation, and identified associated functional changes. Propensity for metastasis was not associated with these subgroups. Using QRT–PCR data we identified a four-gene model (PSMD10, HSD17B12, FLOT2 and KRT17) that predicts M/NM status with 77% success in a separate 79-sample validation group of HNSCC samples. This prediction is independent of clinical criteria (age, lymph node status, stage, differentiation and localization). The most significantly altered transcripts in M versus NM were significantly associated to metastasis-related functions, including adhesion, mobility and cell survival. Several genomic modifications were significantly associated with M/NM status (most notably gains at 4q11–22 and Xq12–28; losses at 11q14–24 and 17q11 losses) and partly linked to transcription modifications. This work yields a basis for the development of prognostic molecular signatures, markers and therapeutic targets for HNSCC metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Applebaum KM, Furniss CS, Zeka A, Posner MR, Smith JF, Bryan J et al. (2007). Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 99: 1801–1810.

    Article  Google Scholar 

  • Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29.

    Article  CAS  Google Scholar 

  • Babuke T, Tikkanen R . (2007). Dissecting the molecular function of reggie/flotillin proteins. Eur J Cell Biol 86: 525–532.

    Article  CAS  Google Scholar 

  • Barker N, Clevers H . (2006). Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discovery 5: 997–1014.

    Article  CAS  Google Scholar 

  • Baudis M, Cleary ML . (2001). Progenetix.net: an online repository for molecular cytogenetic aberration data. Bioinformatics 17: 1228–1229.

    Article  CAS  Google Scholar 

  • Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E et al. (2007). Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45: 42–52.

    Article  CAS  Google Scholar 

  • Braakhuis BJ, Senft A, de Bree R, de Vries J, Ylstra B, Cloos J et al. (2006). Expression profiling and prediction of distant metastases in head and neck squamous cell carcinoma. J Clin Pathol 59: 1254–1260.

    Article  CAS  Google Scholar 

  • Carles A, Millon R, Cromer A, Ganguli G, Lemaire F, Young J et al. (2006). Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display. Oncogene 25: 1821–1831.

    Article  CAS  Google Scholar 

  • Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D et al. (2004). Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5: 489–500.

    Article  CAS  Google Scholar 

  • Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, Lemaire F et al. (2004). Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene 23: 2484–2498.

    Article  CAS  Google Scholar 

  • Dawson S, Higashitsuji H, Wilkinson AJ, Fujita J, Mayer RJ . (2006). Gankyrin: a new oncoprotein and regulator of pRb and p53. Trends Cell Biol 16: 229–233.

    Article  CAS  Google Scholar 

  • Dupuy A, Simon RM . (2007). Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J Natl Cancer Inst 99: 147–157.

    Article  Google Scholar 

  • Esteller M . (2007). Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298.

    Article  CAS  Google Scholar 

  • Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, Frakes A et al. (2006). Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res 66: 6665–6674.

    Article  CAS  Google Scholar 

  • Forastiere A, Koch W, Trotti A, Sidransky D . (2001). Head and neck cancer. N Engl J Med 345: 1890–1900.

    Article  CAS  Google Scholar 

  • Glas AM, Floore A, Delahaye LJ, Witteveen AT, Pover RC, Bakx N et al. (2006). Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 7: 278.

    Article  Google Scholar 

  • Gollin SM . (2001). Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease. Head Neck 23: 238–253.

    Article  CAS  Google Scholar 

  • Gu LH, Coulombe PA . (2007). Keratin function in skin epithelia: a broadening palette with surprising shades. Curr Opin Cell Biol 19: 13–23.

    Article  CAS  Google Scholar 

  • Han C, Liu H, Liu J, Yin K, Xie Y, Shen X et al. (2005). Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex. Nucleic Acids Res 33: 6555–6565.

    Article  CAS  Google Scholar 

  • Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP et al. (2007). Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99: 777–789.

    Article  Google Scholar 

  • Ioannidis JP . (2007). Is molecular profiling ready for use in clinical decision making? Oncologist 12: 301–311.

    Article  Google Scholar 

  • Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4: 249–264.

    Article  Google Scholar 

  • Jarvinen AK, Autio R, Haapa-Paananen S, Wolf M, Saarela M, Grenman R et al. (2006). Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses. Oncogene 25: 6997–7008.

    Article  Google Scholar 

  • Kaklamani VG, Gradishar WJ . (2006). Gene expression in breast cancer. Curr Treat Options Oncol 7: 123–128.

    Article  Google Scholar 

  • Le Tourneau C, Velten M, Jung GM, Bronner G, Flesch H, Borel C . (2005). Prognostic indicators for survival in head and neck squamous cell carcinomas: analysis of a series of 621 cases. Head Neck 27: 801–808.

    Article  Google Scholar 

  • Ludwig JA, Weinstein JN . (2005). Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 5: 845–856.

    Article  CAS  Google Scholar 

  • Nguyen DX, Massague J . (2007). Genetic determinants of cancer metastasis. Nat Rev Genet 8: 341–352.

    Article  CAS  Google Scholar 

  • Ragin CC, Taioli E, Weissfeld JL, White JS, Rossie KM, Modugno F et al. (2006). 11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours. Br J Cancer 95: 1432–1438.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Roepman P, Kemmeren P, Wessels LF, Slootweg PJ, Holstege FC . (2006). Multiple robust signatures for detecting lymph node metastasis in head and neck cancer. Cancer Res 66: 2361–2366.

    Article  CAS  Google Scholar 

  • Roepman P, Wessels LF, Kettelarij N, Kemmeren P, Miles AJ, Lijnzaad P et al. (2005). An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet 37: 182–186.

    Article  CAS  Google Scholar 

  • Sanderson JT . (2006). The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol Sci 94: 3–21.

    Article  CAS  Google Scholar 

  • Schlecht NF, Burk RD, Adrien L, Dunne A, Kawachi N, Sarta C et al. (2007). Gene expression profiles in HPV-infected head and neck cancer. J Pathol 213: 283–293.

    Article  CAS  Google Scholar 

  • Simonin F, Karcher P, Boeuf JJ, Matifas A, Kieffer BL . (2004). Identification of a novel family of G protein-coupled receptor associated sorting proteins. J Neurochem 89: 766–775.

    Article  CAS  Google Scholar 

  • Slebos RJ, Yi Y, Ely K, Carter J, Evjen A, Zhang X et al. (2006). Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res 12: 701–709.

    Article  CAS  Google Scholar 

  • Sobin LH, Fleming ID . (1997). TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 80: 1803–1804.

    Article  CAS  Google Scholar 

  • Song D, Liu G, Luu-The V, Zhao D, Wang L, Zhang H et al. (2006). Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study. J Steroid Biochem Mol Biol 101: 136–144.

    Article  CAS  Google Scholar 

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. (2005). Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102: 15545–15550.

    Article  CAS  Google Scholar 

  • van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi O, Kononen J et al. (2002). Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol 161: 1991–1996.

    Article  CAS  Google Scholar 

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034.

    Article  Google Scholar 

  • Vilar M, Murillo-Carretero M, Mira H, Magnusson K, Besset V, Ibanez CF . (2006). Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle. EMBO J 25: 1219–1230.

    Article  CAS  Google Scholar 

  • Zhou X, Temam S, Oh M, Pungpravat N, Huang BL, Mao L et al. (2006). Global expression-based classification of lymph node metastasis and extracapsular spread of oral tongue squamous cell carcinoma. Neoplasia 8: 925–932.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are extremely thankful for the important contributions made by Jaqueline Godet (CIT project scientific manager), the CIT platforms (Affymetrix IGBMC: Philippe Kastner, Christelle Thibault, Doulaye Dembélé; BAC arrays IGBMC: Stan du Manoir, Christelle Arnold; QRT–PCR RNA analysis St Louis: Jessica Zucmann-Rossi), Christine Macabre (technical help), Fabien Petel (data submission to EBI), the IGBMC core facilities and Guy Bronner (providing tumour samples).

Financial support: Ligues Nationale et Régionales (Bas et Haut Rhin) contre le Cancer, CNRS, INSERM.

Author information

Author notes

  1. D S Rickman

    Present address: 4Current address: Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, 1300 York Avenue, Room C-458D, New York, NY 10021, USA.,

Authors and Affiliations

  1. Ligue Nationale Contre le Cancer, Paris, France

    D S Rickman, A De Reynies & E Thomas

  2. Centre Régional de Lutte Contre le Cancer Paul Strauss, 3 rue Porte de l’Höpital, Strasbourg, France

    R Millon, D Muller & J Abecassis

  3. IGBMC CNRS/INSERM/ULP, Illkirch, France

    C Wasylyk & B Wasylyk

Authors
  1. D S Rickman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Millon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A De Reynies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Wasylyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Abecassis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Wasylyk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Wasylyk.

Additional information

Supplementary information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rickman, D., Millon, R., De Reynies, A. et al. Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene 27, 6607–6622 (2008). https://doi.org/10.1038/onc.2008.251

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.251

Keywords

This article is cited by

Search

Advanced search

Quick links