An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas

Abstract

Metastasis is the process by which cancers spread to distinct sites in the body. It is the principal cause of death in individuals suffering from cancer. For some types of cancer, early detection of metastasis at lymph nodes close to the site of the primary tumor is pivotal for appropriate treatment. Because it can be difficult to detect lymph node metastases reliably, many individuals currently receive inappropriate treatment. We show here that DNA microarray gene-expression profiling can detect lymph node metastases for primary head and neck squamous cell carcinomas that arise in the oral cavity and oropharynx. The predictor, established with an 82-tumor training set, outperforms current clinical diagnosis when independently validated. The 102 predictor genes offer unique insights into the processes underlying metastasis. The results show that the metastatic state can be deciphered from the primary tumor gene-expression pattern and that treatment can be substantially improved.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: A predictor for HNSCC lymph node metastasis.
Figure 2: Long-term tissue storage results in loss of predictive accuracy.
Figure 3: The predictor outperforms current clinical diagnosis on the validation set.

References

  1. 1

    Sankaranarayanan, R., Masuyer, E., Swaminathan, R., Ferlay, J. & Whelan, S. Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res. 18, 4779–4786 (1998).

    CAS  PubMed  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Pantel, K. & Brakenhoff, R.H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Robbins, K.T. et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery. Arch. Otolaryngol. Head Neck Surg. 128, 751–758 (2002).

    Article  Google Scholar 

  5. 5

    Woolgar, J.A. Pathology of the N0 neck. Br. J. Oral Maxillofac. Surg. 37, 205–209 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Jones, A.S., Phillips, D.E., Helliwell, T.R. & Roland, N.J. Occult node metastases in head and neck squamous carcinoma. Eur. Arch. Otorhinolaryngol. 250, 446–449 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Pillsbury, H.C. 3rd & Clark, M. A rationale for therapy of the N0 neck. Laryngoscope 107, 1294–1315 (1997).

    Article  Google Scholar 

  8. 8

    Short, S.O., Kaplan, J.N., Laramore, G.E. & Cummings, C.W. Shoulder pain and function after neck dissection with or without preservation of the spinal accessory nerve. Am. J. Surg. 148, 478–482 (1984).

    CAS  Article  Google Scholar 

  9. 9

    van Wilgen, C.P., Dijkstra, P.U., Nauta, J.M., Vermey, A. & Roodenburg, J.L. Shoulder pain and disability in daily life, following supraomohyoid neck dissection: a pilot study. J. Craniomaxillofac. Surg. 31, 183–186 (2003).

    Article  Google Scholar 

  10. 10

    Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Valk, P.J. et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N. Engl. J. Med. 350, 1617–1628 (2004).

    CAS  Article  Google Scholar 

  14. 14

    van't Veer, L.J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Clark, E.A., Golub, T.R., Lander, E.S. & Hynes, R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Saha, S. et al. A phosphatase associated with metastasis of colorectal cancer. Science 294, 1343–1346 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Ramaswamy, S., Ross, K.N., Lander, E.S. & Golub, T.R. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Chung, C.H. et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5, 489–500 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Tumor Analysis Best Practices Working Group. Expression profiling-best practices for data generation and interpretation in clinical trials. Nat. Rev. Genet. 5, 229–237 (2004).

  20. 20

    Simon, R., Radmacher, M.D., Dobbin, K. & McShane, L.M. Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. J. Natl. Cancer Inst. 95, 14–18 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Matsuo, S. et al. Preservation of pathological tissue specimens by freeze-drying for immunohistochemical staining and various molecular biological analyses. Pathol. Int. 49, 383–390 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Fidler, I.J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Pollard, J.W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Chambers, A.F., Groom, A.C. & MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Huang, Q. et al. Genetic differences detected by comparative genomic hybridization in head and neck squamous cell carcinomas from different tumor sites: construction of oncogenetic trees for tumor progression. Genes Chromosomes Cancer 34, 224–233 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Freier, K. et al. Tissue microarray analysis reveals site-specific prevalence of oncogene amplifications in head and neck squamous cell carcinoma. Cancer Res. 63, 1179–1182 (2003).

    CAS  PubMed  Google Scholar 

  27. 27

    Jones, A.S., Roland, N.J., Field, J.K. & Phillips, D.E. The level of cervical lymph node metastases: their prognostic relevance and relationship with head and neck squamous carcinoma primary sites. Clin. Otolaryngol. 19, 63–69 (1994).

    CAS  Article  Google Scholar 

  28. 28

    Hahn, S.S., Spaulding, C.A., Kim, J.A. & Constable, W.C. The prognostic significance of lymph node involvement in pyriform sinus and supraglottic cancers. Int. J. Radiat. Oncol. Biol. Phys. 13, 1143–1147 (1987).

    CAS  Article  Google Scholar 

  29. 29

    Takes, R.P. et al. Expression of genetic markers in lymph node metastases compared with their primary tumours in head and neck cancer. J. Pathol. 194, 298–302 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Jones, K.R., Lodge-Rigal, R.D., Reddick, R.L., Tudor, G.E. & Shockley, W.W. Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch. Otolaryngol. Head Neck Surg. 118, 483–485 (1992).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank D. van Leenen, M. Groot-Koerkamp and J. van Helvoort for microarray production and technology optimization; M. Verdaasdonk for assistance with biopsies; A. Leijen for computer assistance and J. van de Peppel for advice and discussion. Work in the group of F.C.P.H. is supported by grants from the Netherlands Organization for Scientific Research and by the European Union fifth framework project TEMBLOR.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Frank C P Holstege.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Study design and procedures overview. (PDF 95 kb)

Supplementary Table 1

Clinical and histological parameters of tumors and patients. (PDF 128 kb)

Supplementary Table 2

Complete list of the 102 HNSCC predictor genes. (PDF 214 kb)

Supplementary Methods (PDF 40 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roepman, P., Wessels, L., Kettelarij, N. et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet 37, 182–186 (2005). https://doi.org/10.1038/ng1502

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing