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Oral Cancer molecular biology and genetics

Many gene alterations have been implicated in the development and progression of oral squamous cell carcinomas and the stages of carcinogenesis have been clearly defined.1,2 Expression of genes involved in DNA repair and the stability of the genome is frequently altered.

Genetic changes commonly observed in oral cancers, include loss of heterozygosity at the site of known or suspected tumour suppressor genes, in particular 3p (FHIT), 9p (CDKN2A) and 17p (TP53). The TP53 gene is mutated in the majority of oral cancers and other genes in the p53 pathway are frequently disrupted, including deletion of CDKN2A.3,4

Gene amplification and overexpression of particular oncogenes is also seen, including the CCND1 locus at 11q13 and the PIK3CA locus at 3q26.3.2 Mutations in Ras genes are commonly observed, although there is considerable variation between different populations. This may be due to exposure to different carcinogens, for example mutations in H-Ras are more frequently observed in patients from India whose cancer is linked to tobacco chewing.5 Telomerase activation, which promotes the survival of cells carrying genetic abnormalities, has also been observed. Overexpression of cyclooxygenase-2 (COX2) and phospho-epidermal growth factor receptor (pEGFR) is also important in carcinogenesis and may provide useful molecular targets for treatment.6

Polymorphisms in genes involved in the metabolism of carcinogens contained in tobacco and alcohol have been linked to individual susceptibilty. The gluthione S-transferase enzymes (GSTM1 and GSTT1) are expressed in oral tissue and play a role in detoxifying certain carcinogens in tobacco. Some studies have suggested that people with a null genotype for either GSTM1 or GSTT1 have a slightly increased risk of oral cancer.3,7 Other enzymes that metabolise carcinogens have also been implicated in oral cancer susceptibility, including cytochrome p450, the N-acetyltranferases and alcohol dehydrogenase, but their role has not been clearly determined.

An increased risk of oral cancer is associated with a number of inherited cancer syndromes, including Li-Fraumeni, Fanconi’s anaemia and xeroderma pigmentosum.8 Some studies have suggested that there is an inherited component to sporadic oral cancer. First-degree relatives of people with oral cancer have been reported to be at greater risk of developing the disease.8 There are difficulties in separating the effects of shared genes from a common environment in family studies, but there is increasing evidence for an inherited genetic component to oral cancer, possibly associated with a greater susceptibility to genetic damage by environmental mutagens. Those with an inherited susceptibility may be more likely to develop multiple primary tumours.9

Genome-wide expression profiling using microarrays is being used to monitor changes during different stages of oral carcinogenesis.2,10Targeting early events in carcinogenesis may help in early detection and treatment of the disease and the use of inhibitors of both COX2 and EGFR is already being investigated for use in both chemoprevention and treatment.6

References

1. Mao, L., W.K. Hong, and V.A. Papadimitrakopoulou, Focus on head and neck cancer. Cancer Cell, 2004. 5(4): p. 311-6.
2. Hunter, K.D., E.K. Parkinson, and P.R. Harrison, Opinion: Profiling early head and neck cancer. Nat Rev Cancer, 2005. 5(2): p. 127-35.
3. Jefferies, S. and W.D. Foulkes, Genetic mechanisms in squamous cell carcinoma of the head and neck. Oral Oncol, 2001. 37(2): p. 115-26.
4. Scully, C., J.K. Field, and H. Tanzawa, Genetic aberrations in oral or head and neck squamous cell carcinoma 2: chromosomal aberrations. Oral Oncol, 2000. 36(4): p. 311-27.
5. Saranath, D., et al., High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India. Br J Cancer, 1991. 63(4): p. 573-8.
6. Lippman, S.M., J. Sudbo, and W.K. Hong, Oral cancer prevention and the evolution of molecular-targeted drug development. J Clin Oncol, 2005. 23(2): p. 346-56.
7. Cheng, L., et al., Glutathione-S-transferase polymorphisms and risk of squamous-cell carcinoma of the head and neck.Int J Cancer, 1999. 84(3): p. 220-4.
8. Prime, S.S., et al.,A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma.Oral Oncol, 2001. 37(1): p. 1-16.
9. Bongers, V., et al., The relation between cancer incidence among relatives and the occurrence of multiple primary carcinomas following head and neck cancer. Cancer Epidemiol Biomarkers Prev, 1996. 5(8): p. 595-8.
10. Arora, S., et al., Identification of differentially expressed genes in oral squamous cell carcinoma. Mol Carcinog, 2005. 42(2): p. 97-108.

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