RESUMEN
Ossifying fibroma (OF) is a benign neoplasm related to bone characterized by a progressive enlargement of the affected jaw. Recently, the candidate tumor suppressor gene HRPT2 was identified and alterations in this gene were related with the Hyperparathyroidism-jaw tumor syndrome that is characterized by parathyroid adenoma or carcinoma, fibro-osseous lesions (mainly OF) of the jaws, and renal lesions. The purpose of the present study was to evaluate the HRPT2 gene in OF. Tumour and blood samples were obtained from 3 patients with OF and one with juvenile ossifying fibroma (JOF). The results demonstrated three novel mutations in two out of three genotyped OF's. Interestingly, one of these patients showed a germ-line mutation after blood analysis. RT-PCR amplification was performed to analyze HRPT2 mRNA expression and only wild-type HRPT2 transcript was found in all tumours. Investigation of the parafibromin protein by immunohistochemistry showed a similar pattern of immunolocalization with strong nuclear and cytoplasmic staining in all cases. In conclusion, the present study shows for the first time mutations of HRPT2 gene in OF and suggests that OF may arise due to haploinsufficiency of the HRPT2 gene.
Asunto(s)
Fibroma Osificante/genética , Genes Supresores de Tumor , Neoplasias Mandibulares/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Femenino , Fibroma Osificante/metabolismo , Expresión Génica , Humanos , Masculino , Neoplasias Mandibulares/metabolismo , Persona de Mediana Edad , Mutación , ARN Mensajero/genética , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteínas Supresoras de Tumor/metabolismoRESUMEN
We report here the genetic findings of a new isolated familial somatotropinoma (IFS) kindred in which the mother (subject I:2) and one daughter (subject II:2) are affected; their ages at diagnosis were 25 and 14 years respectively. Additionally, patient I:2 developed virilization due to an androgen-secreting adrenocortical mass, presenting clinical and molecular features of sporadic adrenal carcinoma. To genotype this family and to narrow down the candidate interval of the putative IFS gene at 11q13, we performed haplotyping on the DNA from all five members of the family and allelotyping of one available somatotropinoma using polymorphic microsatellite markers from chromosome region 11q12.1-11q13.5. Results indicated that the disease haplotype, between markers D11S956 and D11S527, was transmitted from subject I:2 only to subject II:2. A meiotic recombination event was detected in the fraternal twin sister of II:2 (subject II:1), but her disease status is unknown. Since she is only 18 years old this genetic event cannot yet narrow down the area involved in the pathogenesis of IFS. Allelotyping of the somatotropinoma from II:2 revealed loss of the chromosome carrying the wild-type copy of the putative IFS gene inherited from her father. These results support the involvement of a tumor suppressor gene at 11q13.1-q13.3 in the pathogenesis of IFS.