Laryngeal Tumors: an overview – Atlas of Genetics and …

Environmental or genetic factors may be responsible for individual susceptibility to LSCC. A genetic predisposition for the development of LSCC is highly probable. Genetic polymorphisms of carcinogen-metabolizing enzymes have been found in tobacco smoke and there is evidence that they are associated with the risk of cancer development of the aerodigestive tract. Polymorphisms of genes encoding for arylamine N-acetyltransferases, human OGG1 DNA repair enzyme, CYP1A1, XRCC and glutathione S-transferases have been evaluated in relation to the risk LSCC development, however with controversial results.

Identification of tumour suppressor genes and proto-oncogenes may be critical for an understanding of the biological initiation and progression of laryngeal cancer. Knowledge about the time course of a single molecular alteration may be helpful in its clinical use for molecular epidemiology, diagnostics or characterisation of laryngeal cancer.

The perfect marker for molecular characterisation of LSCC should have the following properties: 1. not be constantly present in malignant cells, 2. associated with precise biological features and predictable clinical behaviour and, 3. easily detected by a standard, simple and reliable method on a small tissue sample. Unfortunately, no such marker yet exists.

Alterations of p53 protein expression and mutations of the p53 gene have been proposed as independent predictors of recurrence in LSCC, however with controversial prognostic value.

p53 protein overexpression has been detected in a high percentage of LSCC correlating well with p53 gene mutation.

p53 gene mutation has been suggested more reliably than p53 protein overexpression for characterisation, predicting also the response to radiotherapy in LSCC patients. This observation is in accordance with the biological role of p53, which mediates apoptosis associated with DNA damage.

Alterations in p53 status have been evaluated in healthy mucosa, precancerous lesions and tumour cells in order to predict the development of LSCC and secondary primary tumours. Mutations of p53 have also been evaluated to detect whether multiple primary tumours have a mono- or polyclonal origin, without however, definitive conclusions.

In LSCC, degradation mediated by other cellular proteins, such as MDM2 or by human papillomavirus (HPV) E6 oncoprotein may represent alternative pathways leading to loss of p53 function.

A p53 gene therapy approach has already been shown to induce apoptosis, radio- and chemosensitisation in cell lines and this, in combination with radiotherapy or chemotherapy, is a rational possibility. Another potential application considered the treatment of dysplastic lesions, as p53 mutations seem to occur early in laryngeal carcinogenesis.

EGFR is frequently and early overexpressed in LSCC, mainly by post-translational mechanisms. EGFR expression retains a strong predictive value independently of treatment (surgery, chemotherapy and radiation) and adversely influences overall relapse-free and metastasis-free survival in LSCC. At present, EGFR is the most reliable biological marker for molecular characterisation, aggressiveness and invasiveness of LSCC.

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Laryngeal Tumors: an overview - Atlas of Genetics and ...