Novel germline mutations of the <i>MEN1</i> gene in Greek families with multiple endocrine neoplasia type 1

Peppa, Μelpomeni; Boutati, Eleni; Kamakari, Smaragda; Pikounis, Vasilios; Peros, Georgios; Koutsodontis, Georgios; Metaxa-Mariatou, Vassiliki; Economopoulos, Theofanis; Raptis, Sotirios A.; Hadjidakis, Dimitrios

doi:10.1111/j.1365-2265.2008.03308.x

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…The aCGH findings indicate a hyperdiploid karyotype, but do not correlate with the complex karyotype (56w79,XX,þX [2],þ1 [3],þ7 [2],þ8 [3],þ9 [3],þ11 [3],þ13 [2],þ14 [3],þ16 [3],þ20 [3],þ22 [2][cp3]; this suggests a near-triploid set, which has been identified previously by karyotyping, although restricted to only three metaphases (33).…”

Section: Discussionmentioning

confidence: 98%

Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

Rusconi¹,

Valtorta²,

Rodeschini³

et al. 2011

Cancer Genetics

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder associated with mutations of the MEN1 gene, which is characterized by combined tumors of the parathyroid glands, pancreatic islet cells, and the anterior pituitary. A significant number of patients with the clinical features of MEN1, however, do not show MEN1 mutations upon direct sequencing. We describe a young woman who fulfilled the clinical and biochemical criteria for MEN1 syndrome, but DNA sequencing did not indicate any MEN1 mutations. She developed a prolactin-secreting pituitary macroadenoma, primary hyperparathyroidism with parathyroid hyperplasia, pancreatic lesions, and two subcutaneous lipomas. Array comparative genomic hybridization (aCGH) analysis of peripheral blood DNA revealed a heterozygous germline deletion at 11q13.1 that spanned at least 22.23 kilobases and contained the entire MEN1 gene. Integrated aCGH and cytogenetic analyses of the adenoma and lipoma tissues revealed somatic inactivation of the wild-type MEN1 allele by different routes: the second hit of MEN1 recessive oncogenesis leading to adenoma implied a loss of heterozygosity, whereas a balanced translocation deleting the wild-type MEN1 allele primed the lipoma development. These findings show that aCGH is a valuable means of optimizing genetic testing in MEN1 patients which complements other technologic approaches to elucidating the pathologic mechanisms of MEN1 tumors. Keywords FISH, aCGH, MEN1, pituitary adenoma, lipoma ª 2011 Elsevier Inc. All rights reserved.Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant monogenic disorder with 95% penetrance that occurs in approximately 1/30,000 people and has an equal gender distribution (1e3). It is characterized by the development of parathyroid adenomas (90e97%), pituitary adenomas (15e50%), and duodenal and/or pancreatic neuroendocrine tumors (30e80%) (4,5). In addition to these major lesions, patients may develop adrenal or thyroid adenomas, bronchial or thymic carcinoid tumors, and (albeit less frequently) various non-endocrine tumors such as lipomas, angiofibromas, collagenomas, and leiomyomas (6,7). The clinical diagnosis is based on the presence of at least two of the three main MEN1-related tumors (8,9), and there are reports of both sporadic (de novo) and familial forms. Familial MEN1 is diagnosed in the setting of a MEN1 case and a first-degree relative with at least one of the main MEN1-related tumors; sporadic MEN1 when there is no family history of MEN1-related tumors (10).The MEN1 causative gene (11) has 10 exons and encodes a 610 amino acid protein known as menin, a ubiquitously expressed nuclear protein that interacts with a number of the proteins (12,13) involved in transcriptional regulation, genome stability, and cell division and proliferation (14,15). MEN1 acts as a tumor suppressor in accordance with the "two-hit" model of hereditary cancer postulated by Knudson:

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Section: Discussionmentioning

confidence: 98%

Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

Rusconi¹,

Valtorta²,

Rodeschini³

et al. 2011

Cancer Genetics

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“…However, it is clear that most of the MEN1 gene mutations found in MEN1 patients would be expected to inactivate or disrupt menin function. Typical of a classical tumor suppressor gene, the spectrum of reported germline MEN1 mutations occur throughout the gene, and yield no strong genotype/phenotype relationships [18]. In addition, somatic mutations in this gene have been found in 12-17% of typical nonfamilial parathyroid adenomas [19][20][21], and some sporadic gastrinomas and insulinomas [22].…”

Section: Discussionmentioning

confidence: 99%

A new frameshift MEN1 gene mutation associated with familial malignant insulinomas

et al. 2010

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MEN-1 is an autosomal dominant familial cancer syndrome characterized by involvement of parathyroid, enteropancreatic endocrine tissues and the anterior pituitary gland. Malignant insulinomas are rare, and therefore, there are few data regarding their clinical presentation and long-term prognosis. In this report we present a large family with malignant insulinoma and hyperparathyroidism with MEN-1 gene mutation analysis. A large family (three generations) with several members affected were evaluated for clinical and biochemical characteristic of MEN-1 syndrome. Genetic analysis for MEN1 gene was carried out in all family members using PCR amplification of coding regions followed by direct sequencing. In three brothers that presented with hypoglycemia, insulinoma was confirmed and two were malignant according to pathology and surgery report. Two of them had hyperparathyroidism too. Mutation screening revealed the presence of a two nucleotide deletion in the exon 2 (c199_200del2). In the current study, the deletion happens early in the sequence, and obviously results in a non-functional gene product. However, it will be helpful to further examine somatic mutations and other genetic markers for a more precise study of genotype-phenotype correlation.

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“…According to the international RET mutation consortium analysis (1), a strong genotype/phenotype correlation has been found between the MEN2 phenotype and the various mutations of the RET gene in contrast to the other known hereditary multiple endocrine neoplasia syndrome, MEN1 (10,15). Mutations related to MEN2A concern mainly the cysteine-rich extracellular domain of the RET encoded in exons 11 (codon 634, 630, 635, 637, and 666) and 10 (codons 609, 611, 618, and 620), leading to RET dimerization and constitutive activation of downstream signaling pathways (1,(3)(4)(5)(6)(7).…”

Section: Discussionmentioning

confidence: 99%

“…MEN2 is caused by germline gain-of-function mutations of the RET proto-oncogene (RET) (2). Mutations affecting the cysteine-rich extracellular domain encoded in RET exons 10-15 have been associated with MEN2A; a single point mutation in RET exons 15 and 16 has been associated with MEN2B; mutations at certain codons in various exons of RET (5,8,(11)(12)(13)(14)(15)(16) have been associated with familial medullary thyroid carcinoma (FMTC) (1,(3)(4)(5)(6)(7). However, the G533C mutation in exon 8 of the RET is a rare mutation and has been mainly associated with FMTC (8).…”

Section: Introductionmentioning

confidence: 99%

Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

Peppa¹,

Boutati²,

Kamakari³

et al. 2008

European Journal of Endocrinology

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Introduction: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene (RET), mainly in exons 10-15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. Patients-methods: We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7-19 and 21, following standard procedures. Results: The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. Conclusion: Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome.

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Novel germline mutations of the MEN1 gene in Greek families with multiple endocrine neoplasia type 1

Abstract: This is the first report to reveal a high prevalence of novel MEN1 gene mutations among Greek MEN1 patients with apparent absence of genotype-phenotype correlation. Because of the small number of patients examined, the high prevalence detected might be a chance phenomenon.

Cited by 8 publications

References 25 publications

Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

A new frameshift MEN1 gene mutation associated with familial malignant insulinomas

Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

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