Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database

Francesca Marini, Francesca Giusti, Caterina Fossi, Federica Cioppi, Luisella Cianferotti, Laura Masi, Francesca Boaretto, Stefania Zovato, Filomena Cetani, Annamaria Colao, Maria Vittoria Davì, Antongiulio Faggiano, Giuseppe Fanciulli, Piero Ferolla, Diego Ferone, Paola Loli, Franco Mantero, Claudio Marcocci, Giuseppe Opocher, Paolo Beck-PeccozLuca Persani, Alfredo Scillitani, Fabiana Guizzardi, Anna Spada, Paola Tomassetti, Francesco Tonelli, Maria Luisa Brandi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: Multiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype–phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date. Methods: The study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases]. Results: We identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation. Conclusions: Our data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis.

Original languageEnglish
Pages (from-to)215-233
Number of pages19
JournalEndocrine
Volume62
Issue number1
DOIs
Publication statusPublished - Oct 1 2018

Fingerprint

Multiple Endocrine Neoplasia Type 1
Databases
Mutation
Exons
Multiple Endocrine Neoplasia
Frameshift Mutation
Time and Motion Studies
Neuroendocrine Tumors
Penetrance
Germ-Line Mutation
Nonsense Codon
Mutation Rate
Pedigree
Carcinogenesis

Keywords

  • Genetic test
  • Genotype–phenotype correlation
  • MEN1 inactivating mutations
  • Multiple endocrine neoplasia type 1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Marini, F., Giusti, F., Fossi, C., Cioppi, F., Cianferotti, L., Masi, L., ... Brandi, M. L. (2018). Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. Endocrine, 62(1), 215-233. https://doi.org/10.1007/s12020-018-1566-8

Multiple endocrine neoplasia type 1 : analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. / Marini, Francesca; Giusti, Francesca; Fossi, Caterina; Cioppi, Federica; Cianferotti, Luisella; Masi, Laura; Boaretto, Francesca; Zovato, Stefania; Cetani, Filomena; Colao, Annamaria; Davì, Maria Vittoria; Faggiano, Antongiulio; Fanciulli, Giuseppe; Ferolla, Piero; Ferone, Diego; Loli, Paola; Mantero, Franco; Marcocci, Claudio; Opocher, Giuseppe; Beck-Peccoz, Paolo; Persani, Luca; Scillitani, Alfredo; Guizzardi, Fabiana; Spada, Anna; Tomassetti, Paola; Tonelli, Francesco; Brandi, Maria Luisa.

In: Endocrine, Vol. 62, No. 1, 01.10.2018, p. 215-233.

Research output: Contribution to journalArticle

Marini, F, Giusti, F, Fossi, C, Cioppi, F, Cianferotti, L, Masi, L, Boaretto, F, Zovato, S, Cetani, F, Colao, A, Davì, MV, Faggiano, A, Fanciulli, G, Ferolla, P, Ferone, D, Loli, P, Mantero, F, Marcocci, C, Opocher, G, Beck-Peccoz, P, Persani, L, Scillitani, A, Guizzardi, F, Spada, A, Tomassetti, P, Tonelli, F & Brandi, ML 2018, 'Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database', Endocrine, vol. 62, no. 1, pp. 215-233. https://doi.org/10.1007/s12020-018-1566-8
Marini, Francesca ; Giusti, Francesca ; Fossi, Caterina ; Cioppi, Federica ; Cianferotti, Luisella ; Masi, Laura ; Boaretto, Francesca ; Zovato, Stefania ; Cetani, Filomena ; Colao, Annamaria ; Davì, Maria Vittoria ; Faggiano, Antongiulio ; Fanciulli, Giuseppe ; Ferolla, Piero ; Ferone, Diego ; Loli, Paola ; Mantero, Franco ; Marcocci, Claudio ; Opocher, Giuseppe ; Beck-Peccoz, Paolo ; Persani, Luca ; Scillitani, Alfredo ; Guizzardi, Fabiana ; Spada, Anna ; Tomassetti, Paola ; Tonelli, Francesco ; Brandi, Maria Luisa. / Multiple endocrine neoplasia type 1 : analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. In: Endocrine. 2018 ; Vol. 62, No. 1. pp. 215-233.
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T2 - analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database

AU - Marini, Francesca

AU - Giusti, Francesca

AU - Fossi, Caterina

AU - Cioppi, Federica

AU - Cianferotti, Luisella

AU - Masi, Laura

AU - Boaretto, Francesca

AU - Zovato, Stefania

AU - Cetani, Filomena

AU - Colao, Annamaria

AU - Davì, Maria Vittoria

AU - Faggiano, Antongiulio

AU - Fanciulli, Giuseppe

AU - Ferolla, Piero

AU - Ferone, Diego

AU - Loli, Paola

AU - Mantero, Franco

AU - Marcocci, Claudio

AU - Opocher, Giuseppe

AU - Beck-Peccoz, Paolo

AU - Persani, Luca

AU - Scillitani, Alfredo

AU - Guizzardi, Fabiana

AU - Spada, Anna

AU - Tomassetti, Paola

AU - Tonelli, Francesco

AU - Brandi, Maria Luisa

PY - 2018/10/1

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N2 - Purpose: Multiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype–phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date. Methods: The study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases]. Results: We identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation. Conclusions: Our data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis.

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