Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions

Cavaco, Branca; Domingues, Rita; Bacelar, M. C.; Cardoso, Maria Helena; Barros, Luísa; Gomes, Leonor; Ruas, M M; Agapito, Ana; Garrao, Antonio; Pannett, A. A. J.; Silva, J. L.; Sobrinho, L. G.; Thakker, Rajesh V.; Leite, Valeriano

doi:10.1046/j.1365-2265.2002.01505.x

Cited by 53 publications

(45 citation statements)

References 28 publications

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“…About 40% of MEN1 mutations are frameshift due to small deletions or insertions (18). MEN1 large germline deletions compromise about 4% of the genetic defects (32), and as it has been previously reported (33,34), they are only detected using gene dose assays. Despite their role in MEN1 syndrome, mutations in this gene have also been identified in about 20% of familial isolated HPT cases (35,36).…”

Section: Discussionmentioning

confidence: 99%

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Alvelos

Vinagre

Fonseca

et al. 2013

European Journal of Endocrinology

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Objective: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases. Design and methods: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27Kip1 , b-catenin and Ki-67 was conducted by immunohistochemistry. Results: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours. Conclusions: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.

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Section: Discussionmentioning

confidence: 99%

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Alvelos

Vinagre

Fonseca

et al. 2013

European Journal of Endocrinology

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“…tions that would not be detected with currently used primer sets, mutations in regulatory or important nonintronic untranslated regions, disease phenocopies not caused by mutations in MEN1, or large deletions that would be missed by gene sequencing. 35 Large deletions have been reported in only 4 families although over 300 mutations have been reported in the medical literature and the Human Gene Mutation Database. 36 Nevertheless, such deletions may be more common in MEN1 than previously believed, and our yield may be increased by the addition of Southern blotting or other gene dosage techniques to our standard procedures.…”

Section: Discussionmentioning

confidence: 99%

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Klein

Salih

Bessoni

et al. 2005

Genetics in Medicine

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Purpose: Based on results of diagnostic MEN1 testing, we have attempted to further define the mutational spectrum of the MEN1 gene and the clinical features most frequently associated with MEN1 mutations. Methods:Mutation testing was performed on blood samples by PCR amplification and sequencing of exons 2 to 10 of the MEN1 gene and the corresponding intron-exon junctions. Pedigree phenotypic information was obtained by written questionnaire. Results: Among 288 presumably unrelated pedigrees, 73 independent mutations were found in 89 families. Five mutations were found in 2 pedigrees, and 4 mutations were seen in more than 2 pedigrees. There were 17 nonsense mutations (23.3%), 2 in-frame deletions (2.7%), 18 frameshift-deletion mutations (24.7%), 10 frameshift-insertion or -duplication mutations (13.7%), 13 splice-site mutations (17.8%), and 13 presumptive

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“…A small percentage of patients who are considered to have the MEN1 syndrome (based on the clinical definition) may not harbor a germline mutation within the coding region of the MEN1 gene (Agarwal et al 1997). Possibly, these patients have mutations in the promoter region or large deletions on chromosome 11q13 (Cavaco et al 2002). Currently, in clinical practice, inconclusive DNA sequencing is followed by multiplex ligationdependent probe amplification analysis for detection of large deletions.…”

Section: Men1 Genementioning

confidence: 99%

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

Pieterman¹,

Conemans²,

Dreijerink³

et al. 2014

Endocrine-Related Cancer

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Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

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Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions

Abstract: Summary

Cited by 53 publications

References 28 publications

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

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