ABSTRACT
The human patched gene (PTCH) functions in both embryologic development and tumor suppression. PTCH mutations have been found in odontogenic keratocysts. However, the expression and localization of the protein product of the gene have not been determined in odontogenic tumors and cysts. We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas. All odontogenic lesions, including two keratocysts with truncating mutations, were positive for PTCH. Different types of lesions had different amounts of staining. Lack of staining was noted in the majority of basal cell carcinomas. Taken together, these data suggest that odontogenic keratocysts arise with heterozygous mutations of the PTCH gene.
Subject(s)
Membrane Proteins/analysis , Neoplasm Proteins/analysis , Odontogenic Cysts/genetics , Odontogenic Tumors/genetics , Amino Acid Sequence , Carcinoma, Basal Cell/chemistry , Carcinoma, Basal Cell/genetics , Genes, Tumor Suppressor , Heterozygote , Humans , Immunoenzyme Techniques , Membrane Proteins/genetics , Molecular Sequence Data , Mutation , Neoplasm Proteins/genetics , Odontogenic Cysts/chemistry , Odontogenic Tumors/chemistry , Patched Receptors , Patched-1 Receptor , Receptors, Cell SurfaceABSTRACT
An odontogenic keratocyst (OKC) is a benign cystic lesion of the jaws that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Recently, the gene for NBCCS was cloned and shown to be the human homologue of the Drosophila segment polarity gene Patched (PTCH), a tumor suppressor gene. The PTCH gene encodes a transmembrane protein that acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues, including tooth. We investigated three cases of sporadic odontogenic keratocysts and three other cases associated with NBCCS, looking for mutations of the PTCH gene. Non-radioactive single-strand conformational polymorphism and direct sequencing of PCR products revealed a deletion of 5 base pairs (bp) in exon 3 (518delAAGCG) in one sporadic cyst as well as mutations in two cysts associated with NBCCS, a nonsense (C2760A) and a missense (G3499A) alteration. This report is the first to describe a somatic mutation of PTCH in sporadic odontogenic keratocysts as well as two novel mutations in cysts associated with NBCCS, indicating a similar pathogenesis in a subset of sporadic keratocysts.
Subject(s)
Membrane Proteins/genetics , Mutation/genetics , Odontogenic Cysts/genetics , Trans-Activators , Adult , Amino Acid Substitution/genetics , Basal Cell Nevus Syndrome/genetics , Base Pairing/genetics , Codon, Nonsense/genetics , Embryonic Induction/genetics , Exons/genetics , Female , Frameshift Mutation/genetics , Gene Deletion , Genes, Tumor Suppressor/genetics , Hedgehog Proteins , Humans , Male , Mutation, Missense/genetics , Patched Receptors , Patched-1 Receptor , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Proteins/genetics , Receptors, Cell Surface , Sequence Analysis, DNA , Signal Transduction/geneticsABSTRACT
Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.
Subject(s)
Carcinoma, Medullary/diagnosis , Carcinoma, Medullary/genetics , Germ-Line Mutation/genetics , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Adolescent , Adult , Carcinoma, Medullary/surgery , Child , DNA Mutational Analysis , Female , Genetic Testing/methods , Genotype , Humans , Middle Aged , Pedigree , Phenotype , Thyroid Neoplasms/surgery , ThyroidectomyABSTRACT
OBJECTIVES AND STUDY DESIGN: Squamous cell carcinomas are common malignancies and a major cause of mortality. The molecular mechanisms involved in tumorigenesis remain largely unknown, but sequence alterations have been identified in coding regions of several genes. Primary squamous cell carcinomas of various tissues (skin, head and neck, esophagus, lung, penis, uterus, and vagina) from 52 patients were analyzed for the presence of mutations within several candidate genes presumably involved in tumorigenesis: Gsalpha, Gi2alpha, GTPase activating protein (GAP), and patched (PTCH) genes. METHODS: Mutational analysis scheme included polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE), single stranded conformational polymorphism (SSCP), and selected sequence analysis. RESULTS AND CONCLUSION: No tumor had any evidence of mutations in any of these analyzed genes. Mutations within these genes do not occur frequently in an unselected population of patients with squamous cell carcinomas.