DEVELOPMENTAL GENES AND CANCER - ROLE OF PATCHED IN BASAL-CELL CARCINOMA OF THE SKIN

Many genes originally identified because of their role in embryonic de velopment are also important in postnatal control of cell growth and d ifferentiation. Mutations in some of these genes have been shown to ca use cancer. Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. More than 750 000 new cases are diagnosed annually, and the incidence is rising. BCCs are slow-growing, locally invasive t umors that rarely metastasize but can result in extensive morbidity th rough local recurrence and tissue destruction. Epidemiologic studies s uggest that sunlight (particularly UVB radiation) is a strong risk fac tor for BCC formation, although other factors are also involved. The n evoid basal cell carcinoma syndrome (NBCCS), a rare genetic disorder, is characterized by predisposition to BCCs and other tumors as well as to a wide range of developmental defects. NBCCS maps to chromosome 9q 22.3, and loss of heterozygosity at this site in both sporadic and her editary BCCs suggests that it functions as a turner suppressor. The ge ne for NBCCS was recently cloned and is the human homologue of the Dro sophila gene ''patched.'' Genetic studies in Drosophila show that patc hed is part of the hedgehog signaling pathway, which is important in d etermining embryonic patterning and cell fate in multiple structures o f the developing embryo. Human patched is mutated in both hereditary a nd sporadic BCCs, and inactivation of this gene is probably a necessar y, if not sufficient, step for BCC formation. Delineation of the bioch emical pathway in which patched functions may lead to rational medical therapy for BCCs and possibly for other tumors associated with NBCCS.