The 11q13 Region. It has been estimated that amplifi­cation of the 11q13 region is one of the most common genetic abnormality of HNSCC. There are four genes located in this region, CCND1, FGF3, FGF4 and EMS1, of which CCND1 has been widely analyzed. The product of the CCND1 gene, cyclin D1 phosphorylates the Rb protein, which leads to a progression of the cell cycle. The activity of cyclin D can be suppressed by a number of tumor suppressor genes such as p16, p21 and p27. It has been estimated that amplification of CCND1 is more often encountered in carcinomas of the pharynx than in tumors of the larynx and the oral cavity [2]. This amplification is a precious prognostic marker, associated with nodal metas­tases, advanced tumor stage, a greater possibility for recur­rence, as well as worse survival rates for patients with oral cavity tumors or pharynx tumors [3,4]. Using the fluores­cent in situ hybridization (FISH) method, it has been de­termined that the percentage of amplification is 36% [4]. It has also been proved that the overexpression of cyclin D1 and 11q13 rearrangements are independent prognostic markers in the development of HNSCC. DNA-amplifica­tion leads to overexpression of the gene product, cyclin D1, but it is considered that additional genetic mecha­nisms in proximity to 11q13 also play a role in tumor initi­ation [3,5].

The c-myc Oncogene. Another important prognostic marker is the expression of c-myc oncogene, located at the 8q24 region. This abnormality is connected with a shorter survival [6] and a lack of association with the grade and stage of tumor progression [2]. It is considered that a ge­netic abnormality in more than one gene is an even worse prognostic marker [4]. Real-time polymerase chain reac­tion (PCR) was used to analyze the copy number of the frequently amplified oncogenes CCND1 and c-myc in relation to the commonly deleted tumor suppressor gene p16 to evaluate the clinical significance. Enhanced gene ratio was detected in both cases. Furthermore, enhance­ment of c-myc:p16 was associated with a shorter disease-free interval as a result of the development of recurrences or metastases [7]. Analysis of head and neck tumors shows that a higher rate of amplification, that is more of a co-amplification between c-myc and CENP-F (centromere protein-F), is observed in larynx tumors. Co-amplification has been proved in 7% of a total of 71 tumor materials, most of which display nodal metastases [8]. There has been no evidence of correlation between CENP-F and clinical pathological parameters, but there is such evi­dence in the nodal metastases.

The erbB Oncogene. The activation of the erbB oncogenes has been documented with a number of tumors, including HNSCC. These genes include erbB-1, whose product EGFR is a transmembrane protein with tyrosine-kinase activity. Overexpression of EGFR has been found in a high percentage of HNSCC, accounting for a bad prognostic marker [4], connected with nodal metastases. It is characteristic of low differentiated tumors. There has been no correlation found between EGFR overexpression and recurrence of the disease or survival. EGFR activation leads to activation of STAT (tyrosine-kinase system), the proteins that initiate the process of cell proliferation [9]. It is considered that overexpression of the products of these genes is characteristic for HNSCC, but the link be­tween STAT activity and survival is yet to be proved.

The high rate of EGFR overexpression in HNSCC (80-100%) gives an opportunity for the development of modern biological treatment against the receptors. “We are in a very exciting time in the treatment of head and neck cancer...” Now we can utilize a variety of therapeu­tic strategies: surgery, radiation, gene therapy, molecular targeted therapy, and chemoprevention. We now have the Army, the Navy, the Air Force and the Marines,” said Professor Dong Moon Shin, co-director of the Head and Neck Cancer Program at the University of Pittsburgh Can­cer Institute, Pittsburgh, PA, USA [10].

Several approaches to block the EGFR in HNSCC have been investigated, including small molecules and monoclonal antibodies. Gefitinib (Iressa) and Cetuximab are a new class of anti-cancer therapy that targets the EFGR receptor. Gefitinib (Iressa) is a small molecule which inhibits the EGFR (tyrosine kinase through compet­itive binding to the ATP) binding site. Cetuximab is a human-chimeric monoclonal antibody, which binds com­petitively to the extracellular receptor site to prevent bind­ing by EGFR ligands [11].

The other widely analyzed gene belonging to the same gene family is the proto-oncogene erbB-2/HER2-NEU. The overexpression of its product is connected with a shorter survival. It is also associated with a low expression of the gene product p27 during analysis of tumors of the oral cavity and the oropharynx. It is considered that the overexpression of this member of the receptor-tyrosine kinase family is a bad prognostic marker of HNSCC. Ap­plication of immunohistochemistry showed overexpression of the HER2-product and FISH analysis showed amplifi­cation of the gene. The results display a lack of connec­tion between HER2 and the tumor stage, tumor develop­ment and survival [12]. Due to the low amplification level of the HER2 gene in HNSCC, the application of Her­ceptin (monoclonal antibody) therapy would be restricted to a small group of patients [2].The expression of the third representative, erbB-3, was studied with the help of PCR-technology and amplification of the gene was not detected [13].