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See detailUnravelling the intra-familial correlations and heritability of tumor types in MEN1, a GTE study.
Thevenon, Julien; Bourredjem, Abderrahmane; Faivre, Laurence et al

in European Journal of Endocrinology (2015), 173(6), 819-826

BACKGROUND: Multiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine ... [more ▼]

BACKGROUND: Multiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the GTE-cohort associated with a mutations in the JunD interacting domain, suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intra-familial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs), pituitary, adrenal, bronchial and thymic tumors (ThNETs) and the presence of metastasis. Intra-familial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intra-familial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and th-NETs. The heritability of these three tumor types was consistently strong and significant with 64% (Standard Error [SE]=0.13; p < 0.001) for pituitary tumor, 65% (SE=0,21; p < 0.001) for adrenal tumors, and 97% (SE=0.41; p=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step towards personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity. [less ▲]

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See detailHigher risk of death among MEN1 patients with mutations in the JunD interacting domain. A Groupe d'étude des Tumeurs Endocrines (GTE) cohort study
Thevenon, Julien; Bourredjem, Abderrahmane; Faivre, Laurence et al

in Human Molecular Genetics (2013)

BackgroundMultiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors ... [more ▼]

BackgroundMultiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities.MethodsWe report on a cohort of MEN1 patients from the Groupe d'etude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totalling 262 families and 806 patients were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families.ResultsAccounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR=1.88: 95%-CI=1.15- 3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR=2.34; 95%-CI=1.23- 4.43).ConclusionThis genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up. [less ▲]

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See detailAryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.
Daly, Adrian ULiege; Vanbellinghen, Jean-François ULiege; Khoo, Sok Kean et al

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 ▲]

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See detailRecherches en production laitière et valorisation du lait.
Blecker, Christophe ULiege; Burny, Philippe ULiege; Fabry, Jules et al

in Annales de Gembloux (1997, January), 102(3º-4º trimestre 1996), 131-181

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