[en] 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Thevenon, Julien
Bourredjem, Abderrahmane
Faivre, Laurence
Bauters, Catherine
Calender, Alain
Lebras, Maelle
Giraud, Sophie
Niccoli, Patricia
Odou, Marie-Francoise
Borson-Chazot, Francoise
Barlier, Anne
Lombard-Bohas, Catherine
Clauser, Eric
Tabarin, Antoine
Pasmant, Eric
Chabre, Olivier
CASTERMANS, Emilie ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Ruszniewski, Philippe
Bertherat, Jerome
Delemer, Brigitte
Christin-Maitre, Sophie
Beckers, Albert ; Université de Liège > Département des sciences cliniques > Endocrinologie
Wermer P. Duality of pancreatogenous peptic ulcer. New England Journal of Medicine 1968 278 397-398.
Brandi ML. Multiple endocrine neoplasia type 1. Reviews in Endocrine & Metabolic Disorders 2000 1 275-282. (doi:10.1023/A:1026562217102)
de Laat JM. Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. Journal of Clinical Endocrinology and Metabolism 2014 99 3325-3333. (doi:10.1210/jc.2014-1560)
Goudet P. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World Journal of Surgery 2010 34 249-255. (doi:10.1007/s00268-009-0290-1)
Triponez F, Dosseh D, Goudet P, Cougard P, Bauters C, Murat A, Cadiot G, Niccoli-Sire P, Chayvialle J-A, Calender A et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Annals of Surgery 2006 243 265-272. (doi:10.1097/01.sla.0000197715.96762.68)
Lévy-Bohbot N, Merle C, Goudet P, Delemer B, Calender A, Jolly D, Thiéfin G, Cadiot G & Groupe des Tumeurs Endocrines. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroentérologie Clinique et Biologique 2004 28 1075-1081. (doi:10.1016/S0399-8320(04)95184-6)
Triponez F, Goudet P, Dosseh D, Cougard P, Bauters C, Murat A, Cadiot G, Niccoli-Sire P, Calender A, Proye Ch et al. Is surgery beneficial for MEN1 patients with small (< orZ2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE World Journal of Surgery 2006 30 654-662.; discussion 663-664. (doi:10.1007/s00268-005-0354-9)
Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Ménégaux F, Chabrier G, Borson-Chazot F, Tabarin A, Bouchard P et al. Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines. European Journal of Endocrinology/European Federation of Endocrine Societies 2011 165 97-105. (doi:10.1530/EJE-10-0950)
Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, Young J, Delemer B, Du Boullay H, Verger MF et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database. European Journal of Endocrinology /European Federation of Endocrine Societies 2012 166 269-279. (doi:10.1530/EJE-11-0679)
Hao W, Skarulis MC, Simonds WF, Weinstein LS, Agarwal SK, Mateo C, James-Newton L, Hobbs GR, Gibril F, Jensen RT et al. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma. Journal of Clinical Endocrinology and Metabolism 2004 89 3776-3784. (doi:10.1210/jc.2003-031511)
Goudet P, Murat A, Cardot-Bauters C, Emy P, Baudin E, du Boullay Choplin H, Chapuis Y, Kraimps J-L, Sadoul J-L & Tabarin A. GTE network (Groupe des Tumeurs Endocrines). Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World Journal of Surgery 2009 33 1197-1207. (doi:10.1007/s00268-009-9980-y)
Sakurai A, Imai T, Kikumori T, Horiuchi K, Okamoto T, Uchino S, Kosugi S, Suzuki S, Suyama K, Yamazaki M et al. Thymic neuroendocrine tumour in multiple endocrine neoplasia type 1: female patients are not rare exceptions. Clinical Endocrinology 2013 78 248-254. (doi:10.1111/j.1365-2265.2012.04467.x)
Lips CJ, Dreijerink KM & Höppener JW. Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation. Clinics 2012 67 49-56. (doi:10.6061/clinics/2012(Sup01)10)
Teh BT, Hayward NK, Walters MK, Shepherd JJ, Wilkinson S, Nordenskjold M & Larsson C. Genetic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Journal of Medical Genetics 1994 31 261-262. (doi:10.1136/jmg.31.3.261)
Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, Daddi G, Puma F, Ribacchi R, Santeusanio F et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. Journal of Clinical Endocrinology and Metabolism 2005 90 2603-2609. (doi:10.1210/jc.2004-1155)
Kouvaraki MA, Lee JE, Shapiro SE, Gagel RF, Sherman SI, Sellin RV, Cote GJ & Evans DB. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Archives of Surgery 2002 137 641-647. (doi:10.1001/archsurg.137.6.641)
Wautot V, Vercherat C, Lespinasse J, Chambe B, Lenoir GM, Zhang CX, Porchet N, Cordier M, Béroud C & Calender A. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Human Mutation 2002 20 35-47. (doi:10.1002/humu. 10092)
Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F & Dralle H. Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clinical Endocrinology 2007 67 613-622. (doi:10.1111/j.1365-2265.2007. 02934.x)
Thevenon J, Bourredjem A, Faivre L, Cardot-Bauters C, Calender A, Murat A, Giraud S, Niccoli P, Odou M-F, Borson-Chazot F et al. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study. Human Molecular Genetics 2013 22 1940-1948. (doi:10.1093/hmg/ddt039)
Keen KJ & Elston RC. Robust asymptotic sampling theory for correlations in pedigrees. Statistics in Medicine 2003 22 3229-3247. (doi:10.1002/sim.1559)
Duggirala R, Williams JT, Williams-Blangero S & Blangero J. A variance component approach to dichotomous trait linkage analysis using a threshold model. Genetic Epidemiology 1997 14 987-992. (doi:10.1002/(SICI)1098-2272(1997)14:6<987::AID-GEPI71>3.0.CO;2-G)
SAGE 2012 Statistical Analysis for Genetic Epidemiology, Release 6.3:http://darwin.cwru.edu
Almasy L & Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics 1998 62 1198-1211. (doi:10.1086/301844)
De Laat JM, Tham E, Pieterman CRC, Vriens MR, Dorresteijn JAN, Bots ML, Nordenskjöld M, van der Luijt RB & Valk GD. Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 167 181-187. (doi:10.1530/EJE-12-0210)
Visscher PM, Hill WG & Wray NR. Heritability in the genomics era - concepts and misconceptions. Nature Review Genetics 2008 9 255-266. (doi:10.1038/nrg2322)
Easton DF, Ponder MA, Huson SM & Ponder BA. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. American Journal of Human Genetics 1993 53 305-313.
Szudek J, Joe H & Friedman JM. Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genetic Epidemiology 2002 23 150-164. (doi:10.1002/gepi.1129)
Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Human Molecular Genetics 2009 18 2768-2778. (doi:10.1093/hmg/ddp212)
Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Journal of Clinical Endocrinology and Metabolism 2012 97 2990-3011. (doi:10.1210/jc.2012-1230)
Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Lévy-Bohbot N, du Boullay H, Bertagna X, Ruszniewski P, Borson-Chazot F et al. MEN1 disease occurring before 21 years old. A 160-patient cohort study from the GTE (Groupe d'étude des Tumeurs Endocrines). Journal of Clinical Endocrinology and Metabolism 2015 160 jc20143659. (doi:10.1210/jc.2014-3659)