RESUMO
The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Hipersecreção Hipofisária de ACTH/genética , Neoplasias Hipofisárias/genética , Adolescente , Criança , Cromograninas , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p27 , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Hipersecreção Hipofisária de ACTH/diagnóstico , Neoplasias Hipofisárias/diagnósticoRESUMO
Heterozygote deletions or mutations of pseudoautosomal 1 region (PAR1) encompassing the short stature homeobox-containing (SHOX) gene cause Leri-Weill Dyschondrosteosis (LWD), which is a dominantly inherited osteochondroplasia characterized by short stature with mesomelic shortening of the upper and lower limbs and Madelung deformity of the wrists. SHOX is expressed by both sex chromosomes in males and females and plays an important role in bone growth and development. Clinically, the LWD expression is variable and more severe in females than males due to sex differences in oestrogen levels. Here, we report two familial cases of LWD with a large Xp terminal deletion (approximately 943 kb) of distal PAR1 encompassing the SHOX gene. In addition, the proband had mental retardation which appeared to be from recessive inheritance in the family.
Assuntos
Nanismo/genética , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Deleção de Sequência , Adolescente , Adulto , Consanguinidade , Epilepsia/genética , Saúde da Família , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Proteína de Homoeobox de Baixa Estatura , SíndromeAssuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Hematológicas/cirurgia , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/cirurgia , Transtornos Mieloproliferativos/cirurgia , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Irradiação Corporal TotalRESUMO
AIMS: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis. METHODS AND RESULTS: Archival biopsy specimens of 39 EECs, 14 cases of atypical hyperplasia (AH), 11 histologically normal endometrial tissues adjacent to EECs and 24 normal control endometrial samples were retrieved. The cases were tested by quantitative methylation-specific polymerase chain reaction with primers hybridizing in the promoter regions of five genes frequently methylated in human cancer (RASSF1A, RARb2, P16, MGMT and GSTPi). Twenty-nine of 39 (74%) EECs and 7/14 (50%) AHs were methylated for the RASSF1A gene, whereas 17/39 (44%) EECs and 6/14 (43%) AHs were positive for the methylation of the RARb2 gene. No significant results were obtained for the other genes (P16, MGMT and GSTPi). Interestingly, 4/11 (36%) and 6/11 (55%) histologically normal endometrial tissues adjacent to EEC showed, respectively, RASSF1A and RARb2 gene methylation. Furthermore, these 11 specimens were microsatellite stable and showed similar proliferative, cell cycle and apoptotic mean labelling indices as the normal endometrial control tissues. CONCLUSIONS: Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis.
