Genetic steps in the development of squamous cell carcinoma of the esophagus

Esophageal squamous cell carcinoma (ESCC) is a frequent form of cancer that shows striking variations in geographic distribution, reflecting exposure to specific environmental factors that are still poorly defined. ESCC devel ops as the result of a sequence of histopathological changes that typically involves esophagitis, atrophy, mild to severe dysplasia, carcinoma in situ and finally, invasive cancer. Genetic changes associated with the developm ent of ESCC include mutation of the p53 gene, disruption of cell-cycle cont rol in G1 by several mechanisms (inactivation of p16MTS1, amplification of Cyclin D1, alterations of RE), activation of oncogenes (e.g., EGFR, c-MYC) and inactivation of several tumor suppressor genes. Loss of heterozygosity on chromosome 17q25 has been linked with tylosis, a rare autosomal dominant syndrome associated with high predisposition to ESCC. Whether this locus i s also involved in sporadic ESCC remains to be elucidated. Chronic esophagi tis is a frequent occurrence in populations at high risk of ESCC. These les ions often show focal accumulation of p53 protein and in some instances. pa tches of positive cells in esophagitis area at the margins of tumors were f ound to contain a mutation in the p53 gene. This observation is consistent with field cancerization in the esophagus and suggests that esophagitis may represent an interesting target for early detection of ESCC as well as for intervention strategies. (C) 2000 Elsevier Science B.V. All rights reserve d.