Figure 3: Loss of heterozygosity

Normal allele

Cancer susceptibility genes

Germline mutation

Epigenetic events: promoter hypermethylation

While oncogenes and tumor suppressor genes involve alterations in the DNA sequence, there are other mechanisms controlling the

_Mutant expression of genes, known as allele epigenetic changes. DNA methylation is one such mechanism. The promoter region of up to 50% of human genes contains cytosine-guanine pairings that exceed the expected frequency just because of chance alone. These areas are known as CpG islands. The 5’ carbon of the cytosine is prone to the addition of a methyl group by a series of poorly understood enzymes known as methyltransferases. When this occurs, a binding complex is recruited which blocks the ability of RNA polymerase to transcribe the following gene. It is thought methylation plays a large role in controlling DNA expression during normal development, when genes need to be turned on and off at precise times. Thus, there is

no true alteration in the sequence of the gene, but it is silenced by promoter hypermethylation. This means of gene silencing fits in well with Knudson’s hypothesis in that 1 allele of a tumor suppressor gene can be deleted or mutated, while another allele is silenced through promoter hypermethylation. Recent studies provide strong evidence that promoter hypermethylation is an important mechanism of tumor suppressor gene silencing in many different tumor models. ¹¹

Heterozygous condition: normal gene balances the mutated gene

Originator: National Cancer Institute Source: www.cancer.gov

In hereditary cancer syndromes, individuals are called heterozygous (having one or more dissimilar gene pairs) because they start life with a germline mutation in one of the alleles linked to cancer susceptibility; however, it is balanced by a normal counterpart. These individuals are predisposed to cancer because all their cells have already sustained the first hit to cancer-linked genes. If the critically needed normal suppressor gene that balances this germline mutation is lost at some time during an individual’s life, a condition called loss of heterozygosity (LOH) occurs.

the DNA of individuals and those with cancer was looking at the coiled structure of the chromosomes. Characteristic banding patterns could be seen with some diseases, including leukemias which often involved translocations of large portions of chromosomal arms which could be readily detected. Cytogenetic techniques have advanced such that one can perform whole genome screens looking for amplifications, deletions, or translocations, or one can focus on very specific chromosomal regions using hybridization techniques. While micro-satellites offer the ability to finely map areas of DNA loss, they cannot detect large chromosomal abnormalities, translocations, or amplifications. Thus, the cytogenetic approach offers a different method of detecting areas of DNA alterations that then can be further investigated by more sensitive and focused techniques.

These cytogenetic techniques have been performed in OSCC and have revealed that there are many gross abnormalities in DNA copy numbers and various translocations that occur. In addition, there have been many findings that have pointed to specific chromosomal regions that seem to be hotspots for either amplification or loss. ^7-10 Future work will be required to elucidate the gene products that might be responsible for carcinogenesis at these particular sites.

In OSCC, there have been many studies detailing the presence of promoter hypermethylation of many known tumor suppressor genes. ¹² From a therapeutic standpoint, it is also appealing in that the normal DNA sequence has not been altered, and the methylation is theoretically a reversible process. Future studies are sure to follow in an effort to identify novel tumor suppressor genes that are silenced solely by methylation and to test the feasibility of novel therapeutic agents that are able to target these genes.

Mitochondrial mutations

The role of mitochondria in cellular function has long been known — oxidative phosphorylation occurs in these structures, but they also have a role in carrying out apoptosis and cellular proliferation, and affect the balance of reactive oxygen species within a cell. The body of litera-