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Eur J Endocrinol. 2015 Dec;173(6):819-26. doi: 10.1530/EJE-15-0691. Epub 2015 Sep 21.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

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CHU de DijonCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, University of Burgundy, EA4271 GAD, Dijon, FranceINSERMCIC1432, Dijon, FranceCentre Hospitalier Universitaire de DijonCentre d'Investigation Clinique, éssais cliniques/épidémiologie clinique, Dijon FranceCentre Hospitalier Régional et Universitaire de LilleService de Médecine interne et Endocrinologie, Clinique Marc Linquette, Lille, FranceHospices Civils de LyonHôpital E. Herriot, Génétique moléculaire et clinique, Lyon, FranceCentre Hospitalier Universitaire de NantesClinique d'Endocrinologie, Nantes, FranceAPHMservice d'Oncologie Médicale, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, FranceCHRU de LilleService d'Hormonologie, Métabolisme-Nutrition, Oncologie, Pôle de Biologie Pathologie Génétique, Université de Lille2, Lille, FranceHospices Civils de Lyon et Université LYON1Groupement hospitalier Est, Fédération d'Endocrinologie, Lyon, FranceAP-HMHôpital la Conception, Laboratoire de Biologie Moléculaire, Marseille, FranceAix-Marseille UniversityCRN2M UMR 7286-CNRS, Marseille, FranceHospices Civils de LyonHôpital E. Herriot, Service d'Oncologie, Lyon, FranceUniversité Paris-DescartesFaculté de Médecine Paris-Descartes-Paris-V, UMR-S970, Paris, FranceAPHPHôpital Cochin, Laboratoire d'Oncogénétique, Paris, FranceCentre Hospitalier Universitaire et Université de Bordeaux 2Service d'Endocrinologie,Hôpital du Haut Levêque, Pessac,FranceAPHPHôpital Cochin, Service de Biochimie et de Génétique Moléculaire,Paris, FranceCentre Hospitalier Universitaire de GrenobleService d'Endocrinologie, Diabète et Maladies métaboliques, Hôpital Michalon, Grenoble,FranceCentre Hospitalier Universitaire de LiègeDomaine Universitaire du Sart-Tilman, University of Liège, Laboratoire de génétique moléculaire, Liège, BelgiumAPHPHôpital Beaujon et Université Paris 7 Denis Diderot, Service de Gastroentérologie-pancréa



MEN1, which is secondary to the 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 Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation 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 intrafamilial correlations and heritability of the six main tumor types in MEN1.


The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.


Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.


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 toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

[Indexed for MEDLINE]

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