Molecular Genetics of Head and Neck Cancer

Lyon L. Gleich, MD, Frank N. Salamone, MD

Disclosures

Cancer Control. 2002;9(5) 

In This Article

Oncogenes

Oncogenes produce proteins that promote cell and tumor growth. The cellular changes necessary for malignant transformation involve the activation of many oncogenes.

The cyclins are proteins that are involved in cell cycle regulation. The cyclin D1 gene product (CCND1, located at 11q13) phosphorylates Rb, leading to cell cycle progression. The activity of cyclin D1 may be inhibited by many tumor suppressor genes including p16, p21, and p27.[65] In assessing cyclin D1, multiple techniques have been used including IHC, fluorescence in situ hybridization (FISH) allowing detection of gene copy number, and Southern blotting techniques allowing quantification of gene copy number.

In head and neck cancers, cyclin D1 has been shown to be amplified in 36% of tumors using FISH and in 18% to 58% of tumors using Southern blotting, and it is overexpressed in 12% to 68% using IHC ( Table 6 ). Studies that showed a relationship between cyclin D1 and outcome found, as expected, that amplification or overexpression was associated with recurrence, nodal metastasis, or death.

Human epidermal growth factor receptor (EGFR, located at 7p12) is a transmembrane protein with intrinsic tyrosine kinase activity expressed primarily on cells of epithelial origin. EGFR regulates cell growth in response to activation by EGF and transforming growth factor- (TGF- ) binding.[78] EGFR is overexpressed in head and neck tumors, leading to increased tyrosine kinase activity and cell proliferation.[79] In addition, tumors can overexpress EGF, causing autocrine stimulation of the EGFR.

EGFR expression is found in a high percentage of head and neck cancers (43% to 62%).[80,81] EGFR expression has been correlated with worse survival; however, the studies are few, and there are negative studies. Blockage of EGFR receptors in cell lines inhibits tumor growth and has led to active clinical trials.[82]

The STAT tyrosine kinase system has recently been the subject of much investigation. Activated EGFR activates STAT proteins through a complex mechanism. The activated STAT then induces cell proliferation.[83]

STAT3 expression and DNA binding are significantly increased in the mucosa of patients with head and neck cancer.[84] In addition, blocking EGFR expression leads to a decrease in STAT3 activation.[85] No studies have been performed to demonstrate an association between STAT activity and head and neck cancer survival, but this kinase appears to be involved in tumor progression.

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