Squamous Cell Carcinoma

Abstract

There are a variety of molecular alterations that are associated with squamous cell carcinoma (SCC), including altered expression and gain of function of oncogenes, loss of tumor suppressor gene function, and epigenetic alterations, such as tumor-acquired aberrant promoter methylation. SCC often has a variety of chromosome gains and losses. Epithelial growth factor receptor (EGFR) is often overexpressed in non-small cell lung cancers and preneoplastic airway lesions. EGFR tyrosine kinase inhibitors (TKIs) have revolutionized first-line pulmonary adenocarcinoma therapy for patients with an EGFR mutation; however, little progress has been made in treatment of SCC, which are usually nonresponsive to EGFR TKI and may be associated with fatal complications if treated with anti-vascular epithelial growth factor therapies. Loss of heterozygosity, the loss of a single parent’s contribution to part of the cell’s genome, frequently indicates in cancers the presence of a tumor suppressor gene in the lost region, for which the remaining copy of the tumor suppressor gene has been inactivated, often by a point mutation. Loss of heterozygosity on chromosome 3p, an important early molecular event in lung carcinogenesis, is found in more than 90% of SCCs. There are distinct regions, thought to contain multiple tumor suppressor genes that are frequently lost. p53 gene dysfunction is the most common and important genetic alteration in lung cancer development, with p53 gene inactivation by mutations or loss of heterozygosity at 17p13 resulting in loss of p53 tumor suppressor functions, thus promoting tumor cell proliferation. p53 loss occurs in the majority of non-small cell lung cancers, and more commonly in SCC than in adenocarcinomas. p53 gene mutations are associated with cigarette smoking, and inactivating p53 gene mutations have been found very early in the carcinogenesis of SCC. Because p53 gene mutations arise in squamous preneoplastic lesions, it is thought that most p53 gene mutations occur before SCC invasion. Telomerase is expressed in most human cancers, including lung cancers. Germ cells and cancer cells maintain telomere length using the enzyme telomerase and are able to divide indefinitely; and the loss of telomere function is thought to accelerate carcinogenesis. Increased telomerase activity in lung cancer and bronchial epithelial dysplasia has been found.