MEN1  gene mutation with parathyroid carcinoma: first report of a familial case

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Abstract

Background

The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI in individuals and not with multiple members within a family.

Methods

We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised.

Results

Screening of the MEN1 gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects.

Conclusions

The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.

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Most cited references 21

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Positional cloning of the gene for multiple endocrine neoplasia-type 1.

S Chandrasekharappa, S Guru, P. Manickam … (1997)

Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and the anterior pituitary. DNA sequencing from a previously identified minimal interval on chromosome 11q13 identified several candidate genes, one of which contained 12 different frameshift, nonsense, missense, and in-frame deletion mutations in 14 probands from 15 families. The MEN1 gene contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript. The predicted 610-amino acid protein product, termed menin, exhibits no apparent similarities to any previously known proteins. The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis.

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Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.

Rajesh Thakker, Manuel C. Lemos (2007)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610-amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. (c) 2007 Wiley-Liss, Inc.

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HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

J D Carpten, C M Robbins, A Villablanca … (2002)

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Connect

Journal ID (iso-abbrev): Endocr Connect

Journal ID (hwp): EC

Title: Endocrine Connections

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Electronic): 2049-3614

Publication date Collection: November 2017

Publication date (Electronic): 26 October 2017

Volume: 6

Issue: 8

Pages: 886-891

Affiliations

[1 ]Medical Genetics IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[2 ]Laboratory of Oncology IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[3 ]Endocrinology IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[4 ]Thoracic Surgery IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[5 ]Department of Emergency and Organ Transplantation Unit of Endocrinology, University Medical School of Bari ‘Aldo Moro’, Bari, Italy

[6 ]Maxillofacial Surgery IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[7 ]Oncoematology IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[8 ]Pathology IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

[9 ]Departments of Medicine Physiology and Human Genetics, McGill University and Metabolic Disorders and Complications, McGill University Health Centre Research Institute, Montreal, Quebec, Canada

[10 ]Departments of Laboratory Medicine and Pathobiology Medicine and Genetics, University of Toronto, Toronto, Ontario, Canada

Author notes

Correspondence should be addressed to V Guarnieri; Email: v.guarnieri@ 123456operapadrepio.it

[*]

(L Cinque and A Sparaneo contributed equally to this work)

Article

Publisher ID: EC170207

DOI: 10.1530/EC-17-0207

PMC ID: 5704445

PubMed ID: 29097378

SO-VID: bc03eacc-47b5-49cc-9955-f16fde5da4a0

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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MEN1 gene mutation with parathyroid carcinoma: first report of a familial case

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Abstract

Background

Methods

Results

Conclusions

Related collections

Bioscientifica Open Endocrinology

Most cited references 21

Positional cloning of the gene for multiple endocrine neoplasia-type 1.

Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

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