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Role of PTCH in Cancer and Development

Studies of molecular basis of hereditary syndromes that involve both cancer predisposition and birth defects may help understand the relationship between neoplasia and development. The PTCH-gene, a human homologue of the Drosophila segment polarity gene patched, is the gene responsible for Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin syndrome, and is a tumor suppressor as well, at least for basocellular carcinomas of the skin (BCCs). Gorlin syndrome patients develop severe tumores (BCCs in particular) and multiple developmental defects, among which keratocysts of the jaws are most often. Materials and methods: DNA from parients peripheral blood leukocytes and matched tumor tissue were used in LOH (Loss of heterozigosity) studies, with polymorphic markers ( D9S196, D9S287, D9S180, D9 S127) and PTCH primers (exons 3, 6, 8, 13, 15, 16) in SSCP (single strand conformational polymorphism) studies. Results: We examined a series of chromosome 9q polymorphisms in tumorous (BCCs and ovarian fibroma) and non-tumorous (jaw cyst) samples from both Gorlin syndrome patients and sporadic cases and detected loss of heterozigosity (LOH) in PTCH region. In Gorlin syndrome cases we found that the cyst lining of jaws lost the normal copy of the PTCH region while retaining the mutant copy. We also found LOH in some sporadic jaw cysts. While is generally recognized for keratocysts, our recent LOH findings seem to indicate that PTCH inactivation might also be responsible for follicular cysts. Conclusion: We searched for LOH in jaw cysts not only in order to test the hypothesis that anomalies in Gorlin syndrome might arise through a two-hit mechanism, but also in order to examine possible involvement of PTCH in formation of various jaw cysts unrelated to Gorlin syndrome. More generally, we looked for indications of PTCH role in manifestations which were not typical for NBCCS in order to contribute to delineation of the hedgehog/patched pathway.

tumor suppressor; cancer; development; jaw cysts; basal cell carcinoma; Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome; PTCH or patched

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