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Hedgehog/patched signaling pathway in tumorigenesis.Somatic mutations and deletions of PTCH gene in ovarian fibromas

The Hedgehog/Patched signaling pathway is a key regulator of oncogenic transformation and also plays a prominent role during mammalian development specially during embryonic development. This dual role is specially visiable in humans with inherited (patched) PTCH mutations in Gorlin syndrome, an autosomal dominant disorder which is characterized by multiple developmental defects and several types of neoplasms including basal cell carcinomas, neural tumors (meduloblastomas) and ovarian fibromas. The functioning of the hedgehog/patched pathway is as follows: within plasma membrane Ptch interacts with Smo(smoothened) inhibiting and thereby blocking expression of target genes (GLI1, PTCH itself, WNT).Binding of Shh (Sonic hedgehog) to Ptch suspends the inhibition of Smo and turns on the expression of target genes. PTCH gene, a human homologue of the Drosophila segment polarity gene patched, maps to chromosome 9q22.3. Loss of heterozygosity (LOH) at this site in both sporadic and hereditary basal cell carcinomas and medulloblastomas suggests that it functions as a tumor suppressor. Those mutations have been seen in those tumors unrelated to the syndrome, also have been find in breast cancer and rhabdomyosarcoma and characteristic changes have been seen in sporadic malformations (jaw cysts). The aim is to confirm the tumor suppressor role of the Ptch in genesis of ovarian fibromas even when they are not syndrome related. DNA was isolated from fresh tissue and blood leukocytes. The DNA samples were typed for several short tandem repeat polymorphisms's spanning chromosome 9q21-q31 in tumors (ovarian fibroma)and matched constitutional tissues. Polymorphic markers D9S127, D9S287, PTCH intra, D9S180 and D9S196 and 14 PTCH exons were used. We screened for allelic loss and by SSCP we have been analyzing variability in PTCH exons. PCR reactions were performed and products were fractionated on 6-12 %polyacrylamide gels. LOH and PTCH region and aberrant SSCP pattern confirmed the expectations that the gene patched has a decisive role in the genesis of ovarian fibromas when they are not syndrome related.

hedgehog; patched; tumor suppressor; tumors; somatic mutations

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