Sandbox SSW

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sargun Singh Walia M.B.B.S.[2]

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief:

Pathophysiology of Oral Cancer

Tumor suppressor genes (TSGs)

• It is understood that oral cavity cancer is the result of allelic imbalance which is caused by chromosomal changes particularly in chromosome 3,9,11 and 17.
• These changes lead to mutation in tumor suppressor genes (TSGs).
• Normally TSGs modulate normal growth.
• Mutation of these TSGs leads to dysfunctional growth control.
• Mutation most commonly occurs in either of the following:
  • Short arm of chromosome 3
  • TSG termed P16 on chromosome 9
  • TSG termed TP53 on chromosome 17
• Cytochrome P450 genotypes is related to mutations in some TSGs and lead to oral squamous cell carcinoma.
• In western countries (eg, United Kingdom, United States, Australia) TP53 mutations are the most common molecular change that leads to oral squamous cell carcinoma.

Oncogenes

• Cancer may also occur if there is mutation to other genes that control cell growth, mainly oncogenes.
• Oncogenes most commonly involved are:
  • Chromosome 11 (PRAD1)
  • Chromosome 17 (Harvey ras [H-ras])
• In eastern countries (eg, India, Southeast Asia), ras oncogenes is a more common cause of oral squamous cell carcinoma.

Carcinogen-metabolizing enzymes

• Carcinogen-metabolizing enzymes are known to cause cancer in some patients.
• Cytotoxic enzymes such as alcohol dehydrogenase result in the production of:
  • Free radicles
  • DNA hydroxylated bases
• These cytotoxic enzymes especially predispose oral squamous cell carcinoma.

Alcohol

Carcinogen-metabolizing enzymes are implicated in some patients. Alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is cytotoxic and results in the production of free radicals and DNA hydroxylated bases; alcohol dehydrogenase type 3 genotypes appear predisposed to OSCC. Cytochrome P450 can activate many environmental procarcinogens. Ethanol is also metabolized to some extent by cytochrome P450 IIEI (CYP2E1) to acetaldehyde. Mutations in some TSGs may be related to cytochrome P450 genotypes and predispose to OSCC. Glutathione S transferase (GST) genotypes may have impaired activity; for example, the null genotype of GSTM1 has a decreased capacity to detoxify tobacco carcinogens. Some GSTM1 and GSTP1 polymorphic genotypes and GSTM1 and GSTT1 null genotypes have been shown to predispose to OSCC. N-acetyltransferases NAT1 and NAT2 acetylate procarcinogens. N-acetyl transferase NAT1*10 genotypes may be a genetic determinant of OSCC, at least in some populations.

Tobacco is a potent risk factor for oral cancer. An interaction occurs between redox-active metals in saliva and the low reactive free radicals in cigarette smoke. The result may be that saliva loses its antioxidant capacity and instead becomes a potent pro-oxidant milieu. ^{null 5}

DNA repair genes are clearly involved in the pathogenesis of some rare cancers, such as those that occur in association with xeroderma pigmentosum, but, more recently, evidence of defective DNA repair has also been found to underlie some OSCCs.

An immune deficiency state may predispose one to a higher risk of developing OSCC, especially lip cancer.

Gross Pathological Findings

Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

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