High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarinoma

in Histopathology (2008), 53(5), 525-532

Aims: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis. <br />Methods and results: Archival biopsy specimens of ... [more ▼]

Aims: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis. <br />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. <br />Conclusions: Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis. [less ▲]

Evidence for neo-generation of T cells by the thymus after non-myeloablative conditioning.

in Haematologica (2008), 93(2), 240-7

BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning ... [more ▼]

BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning. DESIGN AND METHODS: Fifty patients were randomized to receive either CD8-depleted (n=22) or non-manipulated (n=28) peripheral blood stem cells. The median patients age was 57 (range 36-69) years. The conditioning regimen consisted of 2 Gy total body irradiation with or without added fludarabine. Twenty patients received grafts from related donors, 14 from 10/10 HLA-allele matched unrelated donors, and 16 from HLA-mismatched unrelated donors. Graft-versus-host disease pro-phylaxis consisted of mycophenolate mofetil and cyclosporine. Immune recovery during the first year after hematopoietic cell transplantation was assessed by flow cytometry phenotyping, analyses of the diversity of the TCRBV repertoire, and quantification of signal-joint T-cell receptor excision circles (sjTREC). RESULTS: CD8-depletion of the graft reduced the recovery of CD8(+) T-cell counts in the first 6 months following transplantation (p<0.0001) but had no significant impact on the restoration of other T-cell subsets. Both sjTREC concentration and CD3(+) T-cell counts increased significantly between day 100 and 365 (p=0.010 and p=0.0488, respectively) demonstrating neo-production of T cells by the thymus. Factors associated with high sjTREC concentration 1 year after transplantation included an HLA-matched unrelated donor (p=0.029), a high content of T cells in the graft (p=0.002), and the absence of chronic graft-versus-host disease (p<0.0001). CONCLUSIONS: Our data suggest that while immune recovery is mainly driven by peripheral expansion of the graft-contained mature T cells during the first months after non-myeloablative transplantation, T-cell neo-generation by the thymus plays an important role in long term immune reconstitution in transplanted patients. [less ▲]

Occurrence of AIP Mutations in Sporidic Pituitary Adenomas and Familial Isolated Pituitary Adenomas Kindreds in Valencia, Spain

in ENDO 2008: 90th Annual Meeting of the Endocrine Society - Abstract book (2008)

Aryl Hydrocarbon Receptor interacting Protein Gene Mutations in Bulgarian FIPA and Young Sporadic Pituitary Adenoma Patients

in ENDO 2008: 90th Annual Meeting of the Endocrine Society - Abstract book (2008)

Germline AIP, MEN1, PRKAR1A, CDKN1B (p27Kip1) and CDKN2C (p18INK4c) gene mutations in a large cohort of pediatric patients with pituitary adenomas occurring in isolation or with associated syndromic features

in ENDO 2008: 90th Annual Meeting of the Endocrine Society - Abstract book (2008)

Genetic Analysis of Rwandan Patients With Cystic Fibrosis-Like Symptoms: Identification of Novel Cystic Fibrosis Transmembrane Conductance Regulator and Epithelial Sodium Channel Gene Variants.

in CHEST (2008)

Background The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CFTR loss of function and of an abnormal interaction between CFTR and ENaC. A few patients were ... [more ▼]

Background The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CFTR loss of function and of an abnormal interaction between CFTR and ENaC. A few patients were described with CF-like symptoms, a single CFTR mutation and an ENaC mutation. Methods To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by dHPLC followed by direct sequencing, whereas the SCNN1A, SCNN1B and SCNN1G subunits of ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation Results Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these 5 patients detected 8 ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S, c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. Conclusion Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations. [less ▲]

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

in Journal of Clinical Endocrinology and Metabolism (2007), 92(5), 1891-1896

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess ... [more ▼]

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA. [less ▲]

Characteristics of familial isolated pituitary adenomas (FIPA) - Review

in Expert Review of Endocrinology & Metabolism (2007), 2(6), 725-733

The familial occurrence of pituitary adenomas has been recognized for many years and currently accounts for approximately 5% of all cases. Molecular, genetic and clinical features of familial pituitary ... [more ▼]

The familial occurrence of pituitary adenomas has been recognized for many years and currently accounts for approximately 5% of all cases. Molecular, genetic and clinical features of familial pituitary adenomas have been well characterized in multiple endocrine neoplasia type 1 (MEN-1) and Carney's complex (CNC), which account for the majority of familial pituitary tumor cases. These conditions are caused by MEN1 and PRKAR1A gene mutations, respectively, and the clinical and pathological features of pituitary pathology in these diseases differ from those of sporadic pituitary tumors. Familial acromegaly has been recognized for many years and, more recently, the clinical features of this clinical phenotype, referred to as isolated familial somatotropinoma, have been clarified. Over the past decade, the concept of non-MEN-1/CNC familial pituitary tumors has been expanded significantly to include all phenotypes, a condition known as familial isolated pituitary adenomas (FIPA). In FIPA, tumors can present homogeneously (same phenotype) or heterogeneously (different tumor phenotypes) within the same family. Compared with sporadic pituitary adenomas, patients with FIPA have a younger age at diagnosis and have larger tumors. The clinical features of FIPA differ from those of MEN-1 in terms of a higher frequency of somatotropinomas and a lower frequency of prolactinomas. The recent discovery of the involvement of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in association with pituitary tumors has provided new information regarding potential mechanisms of tumorigenesis in FIPA patients. While very infrequent in sporadic pituitary tumors, approximately 15% of FIPA patients have AIP mutations, rising to half of patients with familial acromegaly. In this review, we detail the clinical features of FIPA and discuss tumor pathology and genetic findings in this increasingly recognized clinical condition. [less ▲]

Néoplasie endocrinienne multiple de type 1 : De la clinique au gène

in Feuillets de Biologie (2003), 44(250), 39-48

La Néoplasie Endocrinienne Multiple de type 1 (NEM 1), syndrome génétique à transmission autosomique dominante, est caractérisée principalement par l'atteinte des parathyroïdes, du tractus gastro-entéro ... [more ▼]

La Néoplasie Endocrinienne Multiple de type 1 (NEM 1), syndrome génétique à transmission autosomique dominante, est caractérisée principalement par l'atteinte des parathyroïdes, du tractus gastro-entéro-pancréatique et de l'antéhypophyse. Les manifestations cliniques de ce syndrome sont polymorphes. En fonction de l'organe affecté elles peuvent se manifester par l'hypersécrétion hormonale, par un syndrome de masse dû à la taille tumorale, ou parfois par l'apparition d'un cancer. Le gène responsable de la NEM 1 a été identifié sur le chromosome 11, locus 11q13. Il s'agit d'un gène supresseur de tumeur qui code pour une protéine dénommée ménine. Dans cet article nous aborderons les aspects cliniques et génétiques typiques de cette affection. [less ▲]

Les adénomes hypophysaires familiaux isolés non liés aux syndromes MEN1 et carney Complex : Etude multicentrique

in Annales d'Endocrinologie : XIXe Congrès de la Société Française d'Endocrinologie - Abstract book (2001)