2737

GLI3

ACLS|GCPS|GLI3-190|GLI3FL|PAP-A|PAPA|PAPA1|PAPB|PHS|PPDIV;GLI family zinc finger 3;GLI3;GLI family zinc finger 3

GLI-Kruppel family member GLI3|glioma-associated oncogene family zinc finger 3|oncogene GLI3|transcriptional activator GLI3|zinc finger protein GLI3

7p13

protein-coding

BACKGROUND: Medulloblastoma is a malignant, invasive embryonic tumor of the cerebellum. Sonic hedgehog (SHH) is a secreted glycoprotein that has a major role in the developing cerebellum. Activation of the SHH pathway resulting from mutations in the PATCH gene, which is an inhibitor of the pathway, are associated with hereditary and sporadic medulloblastomas. The GLI3 protein is another negative regulator of SHH signaling. The authors hypothesized that mutations in GLI3 may be associated with meduloblastomas. METHODS: The authors describe a patient with hereditary Greig syndrome, which was caused by mutations in GLI3, and medulloblastoma. Another such patient was described in the literature. They also sequenced the GLI3 gene, including ALL exon-intron boundaries, in an additional 12 sporadic medulloblastomas. RESULTS: The authors detected a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma. This mutation generates a stop codon in position 809 of GLI3 that has been predicted to result in massive truncation of the protein. Several new polymorphisms, but no tumor-associated mutations, were found in sporadic tumors.CONCLUSIONS: Gli3 is mutated rarely in medulloblastoma.#CI- Copyright 2002 American cancer Society.

The gli gene, originally identified by its amplified copy number in cells from ahuman malignant glioma, has a predicted translation product that contains five tandem DNA-binding zinc finger motifs related to those of Kruppel, a developmentally important Drosophila segmentation gene. Because of the potentialimportance of overproduction of this protein in neoplastic development, we examined DNAs from 29 cases of childhood sarcoma for evidence of amplification of the gli gene. In one of the 13 rhabdomyosarcomas studied, genomic DNA restriction fragments containing the gli gene were amplified approximately 30-fold, and expression of the 4.0-kilobase gli mRNA transcript was identified. The tumor with gli gene amplification lacked the usual histological features of alveolar or embryonal rhabdomyosarcoma; however, ultrastructural analysis of tumor cells established in culture revealed attenuated sarcomeres, resembling those found inprimitive rhabdomyoblasts. Cytogenetic analysis of this cell line disclosed double-minute chromatin bodies, with no apparent rearrangements in the region ofthe gli locus on the long arm of chromosome 12, bands q13 to q14.3. A 15-fold level of gli amplification and gli mRNA transcripts were also detected in an established cell line from a patient with a rare form of osteosarcoma characterized by multipotential histological features. A similar level of gli gene amplification was observed in cryopreserved primary tumor cells from this patient, confirming that gene amplification took place during tumor development and not during in vitro cell culture. Amplified gli sequences were cytogenetically localized by in situ hybridization to a homogeneously staining region contained on a derivative chromosome 7. Of eight osteosarcomas and seven Ewing's sarcomas with typical histopathological features, none had detectable rearrangements or amplification of gli sequences. Thus, gli gene amplification in childhood sarcomas appears restricted to tumors with primitive histopathologicalfeatures, perhaps reflecting overproduction of a gene product able to influence gene expression during early mesenchymal cell development.