Molecular Genetics of Head and Neck Cancer

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

Disclosures

Cancer Control. 2002;9(5) 

In This Article

Tumor Suppressor Genes

Tumor suppressor genes have been intensely investigated in head and neck cancer. These genes act to limit growth of tumors by slowing or halting cell cycle progression, and mutations in tumor suppressor genes are commonly seen in head and neck cancer. Aberrations in specific tumor suppressor genes may be predictive of patient outcome.

Dysfunction in the p53 tumor suppressor gene (located at 17p13) is implicated in many cancers, including head and neck cancer, and has received the most attention. The production of p53 is increased in response to cellular insults or DNA damage, and p53 then induces cell cycle arrest at the G1/S junction. If the damage is irreparable, p53 can initiate cell death by apoptosis.[1]

The steady-state concentration of p53 in normal cells is low, and the half-life of normal (wild type) p53 is short. In contrast, if the p53 gene is mutated, the genetic product is often present in high concentrations.[2] Therefore, immunohistochemical (IHC) methods can be used to detect abnormal p53, although the exact protein that is stained is of questionable significance. Polymerase chain reaction (PCR)-based methods, such as direct sequencing of the p53 gene or loss of heterozygosity (LOH) analysis, also allow detection of mutant p53. LOH analysis detects the loss of a genome-specific allele and thus can detect changes that may not be apparent with IHC analysis.

In head and neck cancer, p53 mutations are present in 33% to 59% of tumors using PCR, LOH occurs in 38% of tumors, and abnormal IHC staining is seen in 37% to 76% of tumors ( Table 1 ). Unfortunately, the tumors that have mutations do not always have abnormal IHC. This poor correlation between PCR analysis, LOH, and IHC is a confounding factor in evaluating head and neck cancer p53 data.

Given the large number of studies without a clear correlation between p53 status and survival, it is evident that mutation of p53 is not a powerful predictive marker. In general, the studies that did show a relationship between p53 and outcome found, as expected, that overexpression of p53 as detected by IHC or the presence of LOH or mutations are associated with recurrence or death. However, an analysis of the Veterans Affairs Laryngeal Cancer Study, in which patients were randomized to induction chemotherapy followed by radiation therapy vs surgery and postoperative radiation, found unexpectedly that p53 overexpression as detected by IHC was associated with an increased rate of organ preservation.[4] A further analysis of these same patients by direct sequencing for mutations reported worse survival with p53 mutations present.[18] The clinical utility of p53 mutations as a predictor of survival or as an aid in selecting the method of therapy is therefore unclear.

Retinoblastoma (Rb, located at 13q14) is a key tumor suppressor gene involved in controlling the cell cycle.[27] Hypophosphorylated Rb binds and inactivates a transcription factor responsible for cell cycle progression (EF1). Mutation of Rb or loss of Rb activity can therefore cause unchecked cell growth.

IHC studies demonstrate Rb abnormalities (diminished expression) in 6% to 74% of head and neck cancers ( Table 2 ). LOH analysis demonstrates loss of an Rb allele in 14% to 59% of tumors. As with p53, there is no clear correlation between Rb mutation and poor outcome; however, two studies suggested that underexpression correlates with poor survival.[28,34] One study found that LOH at p53 and Rb occurring simultaneously is associated with poorer survival.[17]

The p16, p21, and p27 tumor suppressor genes act to modulate cell proliferation. The p16 gene (located at 9p21) produces p16 protein, which in turn inhibits phosphorylation of Rb, thus inhibiting the Rb-induced release of transcription factor EF1 and cell cycle progression.[40] The p21 and p27 genes (located at 6p21 and 14q32, respectively) produce proteins that are activated by p53 and induce cell cycle arrest.[41,42] Abnormalities can be found using PCR, LOH analysis, or Western blotting, which can evaluate protein expression.

Abnormalities in p16 are common in head and neck cancers. PCR methods have shown mutations in 19% to 58% of tumors, while LOH analysis revealed allelic losses in 57% ( Table 3 ). IHC methods have shown low p16 expression in 55% to 89% of tumors. Low expression of p16 therefore occurs in the vast majority of head and neck cancers. A study examining p16 using PCR and Western blotting for the same set of tumors found mutated p16 in only 19% of tumors; however, decreased p16 expression was found in 69% of tumors.[39] Thus, aberrations in the regulation of p16 protein production are common in head and neck cancer. Transcriptional inactivation by hypermethylation of the p16 gene promoter may contribute to this down-regulation.[48,49] Abnormal p16 is associated with worse survival, increased recurrences, tumor progression, and nodal metastasis in many of the studies assessing patient outcome.

Expression of p21 was shown in 29% to 92% of head and neck tumors using IHC methods ( Table 4 ). There is no clear relationship between p21 staining and clinical parameters. Expression of p27 was demonstrated in 18% to 62% of tumors by IHC. The presence of p27 has been correlated with improved survival ( Table 5 ).

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