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1.3. Genes causing head and neck cancer

Cancer, including head and neck squamous cell carcinoma, arises by the accumulation of genetic and epigenetic changes in the DNA, leading to activation of oncogenes and inactivation of tumor suppressor genes and/or DNA stability genes. Recently, we showed that the progression of head and neck cancer can be summarized in four discrete steps that are of pathobiological and clinical importance:

1) one or more genetic hits in a clonal unit in the mucosal epithelium lead to a so called "patch",
2) by more subsequent hits a large precancerous lesion, a so called "field", develops,
3) by further genetic progression the invasive carcinoma arises, and
4) finally metastases develop.

Currently we are investigating the specific genetic alterations that are associated with these discrete steps, and aim to identify all the critical genes. The onset of genetic changes might be chemical carcinogens such as those in tobacco smoke, but also viral infection, and recently we showed that the human papillomavirus (HPV) plays a causative role in approximately 10% of  the oral and oropharyngeal tumors. In addition, we generated an in vitro carcinogenesis model of mucosal keratinocytes. This model allows

1) the analysis of putative cancer genes in relation to replicative lifespan and
2) the screening for novel cancer genes using a functional genomics approach.

  • Braakhuis BJM., Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 2003, 63: 1727-1730.
  • Pantel K, Brakenhoff RH. Dissecting the metastic cascade. Nat Cancer Rev 2004; 4: 448-456.
  • Pantel K, Brakenhoff RH. Burkhard B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nature Reviews Cancer volume 8: May 2008.
  • Smeets SJ, Hesselink AT, Speel EJM, Haesevoets A, Snijders PJF, Pawlita M, Meijer CJLM, Braakhuis BJM, Leemans CR, Brakenhoff RH. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int.J.Cancer 2007: 121, 2465-2472.
  •  Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, Kummer JA, Leemans CR, Braakhuis BJ. Genetically altered fields as origin of locally recurrent head and neck cancer: a retrospective study. Clin Cancer Res 2004; 10: 3607-3613.
  • Van Houten VM, Leemans CR, Kummer JA, Dijkstra J, Kuik DJ, van den Brekel MW, Snow GB, Brakenhoff RH. Molecular diagnosis of surgical margins and local recurrence in head and neck cancer patients: a prospective study. Clin Cancer Res 2004; 10: 3614-3620.
  • Braakhuis BJM, Snijders PJF, Keune W-JH, Meijer CJLM, Ruijter-Schippers HJ, Leemans CR, Brakenhoff RH. Distinct genetic pathway in head and neck cancer containing transcriptionally active Human Papillomavirus. J Natl Cancer Inst 2004, 96: 998-1006.
  • Smeets SJ, Braakhuis BJM, Abbas S, Snijders PJF, Ylstra B, van de Wiel MA, Meijer GA, Leemans CR, and Brakenhoff RH. Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 2006; 25: 2558-64.  
  • Marlon Lindenbergh-van der Plas, Ruud H. Brakenhoff, Dirk J. Kuik, et al.Prognostic Significance of Truncating TP53 Mutations in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 2011;17:3733-3741 . Published OnlineFirst April 5, 2011
  • Sanne R. Martens-de Kemp, Remco Nagel, Marijke Stigter-van Walsum, et al. Functional Genetic Screens Identify Genes Essential for Tumor Cell; Survival in Head and Neck and Lung Cancer.
    Clin Cancer Res 2013;19:1994-2003 . Published OnlineFirst February 26, 2013