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; Ferollà, 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

doi:10.1007/s12020-018-1566-8

Cited by 25 publications

(30 citation statements)

References 51 publications

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“…Until recently, mutations in coding region and splicing sites of MEN1 have been usually investigated by SS complemented by MLPA for large deletions. However, SS presents limitations in the analysis of the MEN1 gene and besides it may not routinely cover the MEN1 non-coding regions (5,8,10,13,18,19,23,28,29,30,56). In addition, it is highly challenging to perform MEN1 testing in the extended number of cases fulling the current criteria for genetic analysis, using SS (5).…”

Section: Discussion Tngs To Detect Men1 Mutationsmentioning

confidence: 99%

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

Carvalho¹,

Urtremari²,

Jorge³

et al. 2018

European Journal of Endocrinology

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Background Loss-of-function germline MEN1 gene mutations account for 75–95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.

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Section: Discussion Tngs To Detect Men1 Mutationsmentioning

confidence: 99%

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

Carvalho¹,

Urtremari²,

Jorge³

et al. 2018

European Journal of Endocrinology

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“…Early genomic analyses identified that approximately 35% of PanNET harboured MEN1 mutations [65,66]. In MEN 1, MEN1 mutations may occur throughout coding regions, commonly with truncating mutations [67]. Physiological menin exerts influence on cell cycle regulation via increasing expression of CDKN2C/CDKN1B (suppresses cell cycle), suppressing the function of PI3K/mTOR pathway signal-ling, and promoting homologous DNA repair which targets double-strand breaks [68].…”

Section: Genomic Landscape Of Pancreatic Netmentioning

confidence: 99%

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

et al. 2019

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The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeu-tic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.According to SEER version 18, SBNEN and PanNEN incidences are currently estimated at 1.2 and 0.7 per 100,000, respectively [5]. The overall 20-year duration prevalence of all NEN is estimated at 171,321; SBNEN constituting 32,122 patients with 3-fold fewer PanNEN (10,707) [5]. Possible attributable factors for this increase evolving epidemiology include increased use of endoscopy and also improvements in the sensitivity of widely used imaging modalities, leading to increased detection of early-stage, asymptomatic disease [5].The median overall survival (OS) for NEN (irrespective of site and grade) is 9.3 years [5]. For SB (median OS: 14 years), this ranges from 70 months (advanced disease with distant metastases) to 170 months (localised disease) and from 30 months (Grade 3) to 160 months (Grade 1). For pancreas (median OS: 3.6 years): 21 months (advanced) to 235 months (localised disease) and from 15 months (Grade 3) to 140 months (Grade 1) [5].Multivariable analyses have identified that ethnicity, age, differentiation, stage and site all have statistically significant correlations with survival. In general, Caucasian ethnicity, age (< 50 years) and localised, well-differentiated NEN exhibit the best survival. SB tumour patients are approximately 1.5 times more likely to survive longer than those with PanNEN [19]. Many of these correlations are self-evident since they pertain to degree of malignancy, disease duration and patient performance status.OS (median 5-year) app...

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“…The disorder has autosomal dominant inheritance with high penetrance and in about 10% may arise from de novo pathogenic variants (144). Pituitary adenomas occur in about 15-50% of MEN1 patients (144,145,146,147,148,149,150,151). The most prevalent pituitary subtypes are prolactinomas (60-80% of the cases), followed by nonfunctioning pituitary adenomas (in more recent seriesup to 42%), or somatotropinomas (in older series -up to 25%) and corticotropinomas (<5%) (144,146,147,148,149).…”

Section: Multiple Endocrine Neoplasia 1 (Men1)mentioning

confidence: 99%

“…A distinctive but uncommon feature of MEN1 pituitary adenomas is the plurihormonal profile (especially prolactin-ACTH and/ or GH-positive tumors on immunohistochemistry), as well as the presence of multiple pituitary adenomas (152,153,154,155). In about 15-30% of patients a pituitary adenoma is the first presentation of MEN1 syndrome (140,147,148,149). Among sporadic pituitary adenomas the occurrence of MEN1 is quite rare -less than 3% (152,156,157).…”

Section: Multiple Endocrine Neoplasia 1 (Men1)mentioning

confidence: 99%

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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

Cited by 25 publications

References 51 publications

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

Somatic and germline mutations in the pathogenesis of pituitary adenomas

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