ABSTRACT
Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
Subject(s)
Carcinoma, Papillary/genetics , Kidney Neoplasms/genetics , Mutation , Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Adult , Aged , Amino Acid Sequence , Binding Sites , Carcinoma, Papillary/epidemiology , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 7 , Female , Genetic Linkage , Germ-Line Mutation , Humans , Kidney Neoplasms/epidemiology , Male , Middle Aged , Molecular Sequence Data , Pedigree , Proto-Oncogene Mas , Proto-Oncogene Proteins c-met , Receptor Protein-Tyrosine Kinases/metabolism , Sequence Homology, Amino AcidABSTRACT
A family with von Hippel-Lindau disease (VHL) type 2A has been shown to have a T to C missense mutation at nucleotide 547 of the VHL gene. This gives further support for the proposal to associate the 547 T to C mutation with phenotype VHL 2A.
Subject(s)
Genes, Tumor Suppressor/genetics , Ligases , Point Mutation/genetics , Proteins/genetics , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , von Hippel-Lindau Disease/genetics , DNA Mutational Analysis , Genotype , Germany/ethnology , Humans , Pennsylvania/epidemiology , Phenotype , Pheochromocytoma/complications , Pheochromocytoma/genetics , Polymorphism, Single-Stranded Conformational , Von Hippel-Lindau Tumor Suppressor Protein , von Hippel-Lindau Disease/complicationsSubject(s)
Dog Diseases/parasitology , Eukaryota/isolation & purification , Protozoan Infections, Animal , Animals , Dog Diseases/pathology , Dogs , Eukaryota/ultrastructure , Lung/parasitology , Lung/pathology , Lymph Nodes/parasitology , Lymph Nodes/pathology , Male , Microscopy, Electron , Protozoan Infections/parasitology , Protozoan Infections/pathology , Skin/parasitology , Skin/pathologyABSTRACT
Sixty-one of 68 sets of bovine lungs from which only Haemophilus somnus was isolated had microscopic lesions of purulent bronchiolitis and bronchopneumonia. In 37 of 61 lungs, the bronchiolar exudates were markedly necrotic with accompanying necrosis of the adjacent bronchiolar epithelium. Bronchiolitis obliterans was prominent in 23 of 28 lungs affected with chronic lesions with abscesses present in seven. Alveolar filling with inflammatory cells (neutrophils with fewer macrophages) was limited to peribronchiolar alveoli in 25 of 61 lungs and was multifocal to diffuse in the other 36. Lesions in the remaining lungs (7 of 68) were classified as fibrinous pneumonia with bronchiolitis (2), fibrinous pleuritis (2), suppurative interstitial pneumonia with vasculitis (2), and diffuse congestion (1).