Multiple Endocrine NeoplasiaSyndromes of the Twentieth Century
Rajesh V. Thakker
MRC Molecular Endocrinology Group
Imperial College School of Medicine
Hammersmith Hospital
London W12 0NN
Address correspondence and requests for reprints to: Professor R.V. Thakker, MRC Molecular Endocrinology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail:
rthakker{at}rpms.ac.uk
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Introduction
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The multiple endocrine neoplasia (MEN) syndrome,
which consists of several subtypes (Table 1
), was first described in the early
1900s, and during the century, the clinical features, biochemical
characteristics, inheritance and genes, together with the encoded
proteins for the MENs, have been defined (reviewed in references 1 and
2). Thus, the MENs represent syndromes of the 20th century,
and the progress in these studies culminating with the four
publications (3, 4, 5, 6) in this issue will be reviewed. MEN is
characterized by the occurrence of tumors involving two or more
endocrine glands within a single patient. This disorder has previously
been referred to as multiple endocrine adenopathy (MEA) and the
pluriglandular syndrome. However, glandular hyperplasia and malignancy
may also occur in some patients, and the term multiple endocrine
neoplasia (MEN) is now the preferred term. There are two major forms of
MEN, type 1 (MEN1, Wermers syndrome) and type 2 (MEN2, Sipples
syndrome); each form is characterized by the development of tumors
within specific endocrine glands (Table 1
). The MEN syndromes are
uncommon, but because they are inherited as autosomal dominant
disorders, the finding of MEN in a patient has important implications
for other family members; first degree relatives have about a 50% risk
of developing the disease. Occasionally, the MEN syndromes may arise
sporadically (i.e. without a family history). It may be
difficult to make the distinction between sporadic and familial forms;
in some cases the family history may be absent because the parent with
the disease may have died before developing any manifestations. Thus,
biochemical and genetic screening may have important roles in the lives
of MEN patients and their families.
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Table 1. The multiple endocrine neoplasia (MEN) syndromes,
their characteristic tumors and associated genetic abnormalities
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Multiple endocrine neoplasia type 1 (MEN1)
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MEN1 is characterized by the combined occurrence of tumors of the
parathyroids, pancreatic islet cells, and anterior pituitary (reviewed
in reference 1). Parathyroid tumors occur in 95% of MEN1 patients,
resulting in the hypercalcemia of primary hyperparathyroidism.
Parathyroid tumors detected by hypercalcemia are the first
manifestation of MEN1 in about 90% of patients. Pancreatic islet cell
tumors occur in 40% of MEN1 patients. Gastrinomas are the most common
type, and insulinomas are the second most common. Glucagonomas and
VIPomas are rare, whereas pancreatic polypeptidomas (PPomas) are more
common but remain asymptomatic. Gastrinomas, leading to the
Zollinger-Ellison syndrome, are the most important cause of morbidity
and mortality in MEN1 patients. Anterior pituitary tumors occur in 30%
of MEN1 patients. Most (60%) are prolactinomas, somatotrophinomas are
the next most common (20%), and corticotrophinomas and nonfunctioning
tumors represent less than 15% of MEN1 pituitary tumors. Associated
tumors, which occur less commonly in MEN1, include adrenal cortical
tumors (5%), carcinoid tumors (4%), lipomas (1%) angiofibromas
(<1%), and collagenomas (<1%).
The MEN1 gene. The gene causing MEN1 was localized to
chromosome 11q13 by genetic mapping studies that investigated MEN1
associated tumors for loss of heterozygosity (LOH) and by segregation
studies in MEN1 families (reviewed in reference 1). The results of
these studies, which were consistent with Knudsons model for tumor
development, indicated that the MEN1 gene represented a putative tumor
suppressor gene. Further genetic mapping studies defined a less than
300 Kb region as the minimal critical segment that contained the MEN1
gene, and characterization of genes from this region led to the
identification of the MEN1 gene (7, 8), which consists of 10 exons with
a 1,830 bp coding region that encodes a novel 610 amino acid protein,
referred to as "MENIN" (7). Mutations of the MEN1 gene have been
identified (7, 8, 9, 10), and the study by Teh et al. (3), in this
issue, reports a further 29 germ-line MEN1 mutations that were found
amongst 58 MEN1 families and 8 sporadic MEN1 patients. Interestingly, a
similar analysis of 8 families with isolated acromegaly and 4 families
with isolated hyperparathyroidism did not detect any germ-line MEN1
mutations (3), and it seems likely that these 2 inherited endocrine
disorders may have a different genetic etiology. The total number of
germ-line mutations of the MEN1 gene that have now been identified (3, 7, 8, 9, 10) in MEN1 patients is approximately 140 and approximately 25% are
nonsense mutations, 45% are deletions, 15% are insertions, less than
5% are donor-splice mutations, and 10% are missense mutations. Thus,
the majority (>80%) of these mutations are inactivating and are
consistent with those expected in a tumor suppressor gene. The
mutations are not only diverse in their types but are also scattered
throughout the 1,830 bp coding region of the MEN1 gene with no evidence
for clustering as observed in MEN2 (see below). However, some of the
mutations have been observed to occur several times in unrelated
families (Table 1
), and the 3 deletional and insertional mutations
involving codons 83 and 84, 209 to 211, and codons 514 to 516, account
for approximately 25% of all the germ-line MEN1 mutations and thus may
represent potential "hot" spots. Such deletional and insertional
hot spots may be associated with DNA sequence repeats that may consist
of long tracts of either single nucleotides or shorter elements,
ranging from dinucleotides to octanucleotides. Indeed, the DNA sequence
in the vicinity of codons 83 and 84 in exon 2, and codons 209 to 211 in
exon 3, contains CT and CA dinucleotide repeats, respectively, flanking
the 4 bp deletions (Table 1
); these would be consistent with a
replication-slippage model in which there is misalignment of the
dinucleotide repeat during replication, followed by excision of the 4
bp single-stranded loop (10). The deletions and insertions of codon 516
involve a poly(C)7 tract, and a slipped-strand mispairing model is also
the most likely mechanism to be associated with this mutational hot
spot (10). Thus, the MEN1 gene appears to contain DNA sequences that
may render it susceptible to deletional and insertional mutations.
Correlations between the MEN1 mutations and the clinical manifestations
of the disorder appear to be absent. For example a detailed study of 5
unrelated families with the same 4 bp deletion (CAGT) in codons 210 and
211 (Table 2
) revealed a wide range of
MEN1-associated tumors (10); all the affected family members had
parathyroid tumors, but members of families 1, 3, 4, and 5 had
gastrinomas, whereas members of family 2 had insulinomas. In addition,
prolactinomas occurred in members of families 2, 3, 4, and 5 but not
family 1, which was affected with carcinoid tumors. More than 10% of
the MEN1 mutations arise de novo and may be transmitted to
subsequent generations (3, 9, 10). It is also important to note that
between 5% to 20% of MEN1 patients may not harbor mutations in the
coding region of MEN1 gene (3, 7, 8, 9, 10), and that these individuals may
have mutations in the promoter or untranslated regions (UTRs), which
remain to be investigated. These together with the wide diversity of
mutations in the 1,830 bp coding region of the MEN1 gene and an
apparent lack of genotype-phenotype correlations, which contrasts with
the situation in MEN2 (see below), will make mutational analysis for
diagnostic purposes in MEN1 time-consuming and expensive.
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Table 2. MEN1 associated tumors in five unrelated families
with a 4bp (CAGT) deletion at codons 210 and 211 (from reference 10)
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MEN1 mutations in sporadic non-MEN1 endocrine tumors.
Parathyroid, pancreatic islet cell, and anterior pituitary tumors may
occur either as part of MEN1 or more commonly as sporadic, nonfamilial,
tumors. Tumors from MEN1 patients have been observed to harbor the
germ-line mutation together with a somatic LOH involving chromosome
11q13, as expected from Knudsons model and the proposed role of the
MEN1 gene as a tumor suppressor. However, LOH involving chromosome
11q13, which is the location of the MEN1, has also been observed in
550% of sporadic endocrine tumors, implicating the involvement of
the MEN1 gene in the etiology of these tumors. This has been
investigated, and the studies by Farnebo et al. (4) and
Carling et al. (5), in this issue, have examined the role of
the MEN1 gene in the etiology of sporadic parathyroid tumors. These
studies (4, 5) revealed that LOH involving chromosome 11q13 and
mutations of the MEN1 gene occurred in less than 30% and less than
15%, respectively, of the sporadic parathyroid tumors (Table 3
). The involvement of the MEN1 gene in
the etiology of sporadic pituitary tumors has also been investigated,
and the study by Tanaka et al. (6), in this issue, reveals
that this is very infrequent at 0.03% (Table 3
). These findings in
sporadic parathyroid (4, 5) and pituitary (6) tumors are in agreement
with those of other reports (11, 13, 14), and the results of all such
studies of sporadic parathyroid tumors, gastrinomas, insulinomas,
anterior pituitary adenomas, carcinoid tumors, and lipomas (Table 3
)
have revealed chromosome 11q13 LOH in 0.0393%, and somatic MEN1
mutations in 0.0336% of these tumors. The occurrence of MEN1
mutations in sporadic parathyroid tumors, gastrinomas, and carcinoid
tumors was greater than that observed in anterior pituitary adenomas.
The tumors harbouring a somatic MEN1 mutation all had chromosome 11q13
LOH as the other genetic abnormality, or "hit," consistent with
Knudsons hypothesis. These studies (4, 5, 6, 11, 12, 13, 14, 15, 16) indicate that
although inactivation of the MEN1 gene may have a role in the etiology
of some sporadic endocrine tumors, the involvement of other genes with
major roles in the etiology of such sporadic endocrine tumors is highly
likely.
Function of MEN1 protein (MENIN). Analysis of the predicted
amino acid sequence encoded by the MEN1 gene did not reveal homologies
to any other proteins, sequence motifs, signal peptides, or consensus
nuclear localization signals (7), and thus, the putative function of
the protein (MENIN) could not be deduced. Recent studies based on
immunofluorescence, Western blotting of subcellular fractions, and
epitope tagging with enhanced green fluorescent protein, have revealed
that MENIN is located primarily in the nucleus (17). Furthermore,
enhanced green fluorescent protein-tagged MENIN deletional constructs
have identified at least two independent nuclear localization signals
that are located in the C-terminal quarter of the protein.
Interestingly, none of the MEN1 germ-line missense or in-frame
deletions (3, 7, 8, 9, 10) alter either of these putative nuclear
localization signals. However, all of the truncated MEN1 proteins that
would result from the nonsense and frameshift mutations, if expressed,
would lack these nuclear localization signals. The nuclear localization
of MENIN suggests that it may act either in the regulation of
transcription, or DNA replication, or the cell cycle. However, the
precise roles of MENIN in the nucleus and in the regulation of
endocrine cell growth control remain to be elucidated.
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Multiple endocrine neoplasia type 2 (MEN2)
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MEN2 describes the association (Table 1
) of medullary
thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors
(reviewed in reference 2). Three clinical variants of MEN2 are
recognizedMEN2a, MEN2b, and MTC-only (Table 1
). MEN2a is the most
common variant, and the development of MTC is associated with
pheochromocytomas (50% of patients), which may be bilateral, and
parathyroid tumors (20% of patients). MEN2b, which represents 5% of
all MEN2 cases, is characterized by the occurrence of MTC and
pheochromocytoma in association with a Marfanoid habitus, mucosal
neuromas, medullated corneal fibers, and intestinal autonomic ganglion
dysfunction leading to multiple diverticulae and megacolon. Parathyroid
tumors do not usually occur in MEN2b. MTC only is a variant in which
medullary thyroid carcinoma is the sole manifestation of the
syndrome.
The MEN2 gene (c-ret). The gene causing all three MEN2
variants was mapped to chromosome 10cen-10q11.2, a region containing
the c-ret proto-oncogene, which encodes a tyrosine kinase
receptor with cadherin-like and cysteine-rich extracellular domains,
and a tyrosine kinase intracellular domain (reviewed in reference 2).
Specific mutations of c-ret have been identified for each of
the three MEN2 variants (Table 1
). Thus, in 95% of patients MEN2a is
associated with mutations of the cysteine-rich extracellular domain,
and mutations in codon 634 account for 85% of MEN2a mutations.
MTC-only is also associated with mutations in the cysteine-rich
extracellular domain, and most mutations are in codon 618. However,
MEN2b is associated with mutations in codon 918 of the intracellular
tyrosine kinase domain in 95% of patients. Interestingly, the
c-ret proto-oncogene is also involved in the etiology of
papillary thyroid carcinomas and in Hirschsprungs disease. Mutational
analysis of c-ret to detect mutations in codons 609, 611,
618, 634, 768, and 804 in MEN2a and MTC-only, and codon 918 in MEN2b,
has been used in the diagnosis and management of patients and families
with these disorders (reviewed in reference 2).
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Conclusions
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The twentieth century has seen enormous advances in the MENs, from
their initial, clinical recognition to identifying the genes and
molecular defects, and in defining some functions of the encoded
proteins. However, many challenges remain. For example, the mutational
diversity of the MEN1 mutations and the apparent lack of
genotype-phenotype correlations, which contrast to that found in MEN2,
require further investigation to bring the benefits of mutational
screening and tumor prevention to the patients. In addition,
elucidating the functional role of MENIN in the nucleus will help to
gain a better understanding of endocrine cell growth and proliferation,
and thereby facilitate the design of potential novel therapies. These
will be some of the challenges for the MEN syndromes in the forthcoming
twenty-first century.
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Acknowledgments
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I am grateful to: the Medical Research Council (MRC), UK, for
support; to my colleagues J.D.H. Bassett, S.A. Forbes, and A.A.J.
Pannett for helpful discussions; and to S. Kingsley for typing the
manuscript.
Received June 2, 1998.
Accepted June 5, 1998.
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References
|
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-
Thakker RV. 1995 Multiple Endocrine Neoplasia
Type 1. In: DeGroot LJ, ed. Endocrinology, 3rd ed.
Philadelphia: WB Saunders; 28152831.
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Gagel RF, Cotes GJ. 1996 Ret
Protooncogene mutations in multiple endocrine neoplasia type 2. In:
Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. San
Diego: Academic Press; 799807.
-
Teh BT, Farnebo F, Phelan C, et al. 1998 Mutation
analysis of the MEN1 gene in multiple endocrine neoplasia type 1,
familial acromegaly, and familial isolated hyperparathyroidism. J
Clin Endocrinol Metab. 83:26212626.[Abstract/Free Full Text]
-
Farnebo F, Teh BT, Kytola S, et al. 1998 Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metabol. 83:26272630.[Abstract/Free Full Text]
-
Carling T, Correea P, Hessman O, et al. 1998 Parathyroid MEN1 gene mutations in relation to clinical
characteristics of nonfamilial primary hyperparathyroidism. J Clin
Endocrinol Metab. 83:29512954.
-
Tanaka C, Kimura T, Yang P, et al. 1998 Analysis
of loss of heterozygosity on chromosome 11 and infrequent inactivation
of MEN1 gene in sporadic pituitary adenomas. J Clin
Endocrinol Metab. 83:26312634.[Abstract/Free Full Text]
-
Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine
neoplasia-type 1. Science. 276:404407.[Abstract/Free Full Text]
-
The European Consortium on MEN1. 1997 Identification of the Multiple Endocrine Neoplasia type 1 (MEN1) gene. Hum Mol Genet. 6:11771183.[Abstract/Free Full Text]
-
Agarwal SK, Kester MB, Debelenko, et al. 1997 Germline mutations of the MEN1 gene in familial multiple endocrine
neoplasia type 1 and related states. Hum Mol Genet. 6:11691175.[Abstract/Free Full Text]
-
Bassett JHD, Forbes SA, Pannett AAJ, et al. 1998 Characterisation of mutations in patients with Multiple Endocrine
Neoplasia Type 1 (MEN1). Am J Hum Genet. 62:232244.[CrossRef][Medline]
-
Heppner C, Kester MB, Agarwal SK, et al. 1997 Somatic mutation of the MEN1 gene in parathyroid tumours. Nature Genet. 16:375378.[Medline]
-
Zhuang Z, Vortmeyer AO, Pack S, et al. 1997 Somatic
mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and
insulinomas. Cancer Res. 57:46824686.[Abstract]
-
Zhuang Z, Ezzat SZ, Vortmeyer AO, et al. 1997 Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer
Res. 57:54465451.[Abstract]
-
Prezant TR, Levine J, Melmed S. 1998 Molecular
characterization of the MEN1 tumor suppressor gene in sporadic
pituitary tumors. J Clin Endocrinol Metab. 83:13881391.[Abstract/Free Full Text]
-
Debelenko LV, Brambilla E, Agarwal SK, et al. 1997 Identification of MEN1 gene mutations in sporadic carcinoid tumors of
the lung. Hum Mol Genet. 6:22852290.[Abstract/Free Full Text]
-
Vortmeyer AO, Boni R, Pak E, et al. 1998 Multiple
endocrine neoplasia 1 alterations in MEN1-associated and sporadic
lipomas. J Nat Cancer Inst. 90:398.[Free Full Text]
-
Guru SC, Goldsmith PK, Burns AL, et al. 1998 Menin,
the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci
USA. 95:16301634.[Abstract/Free Full Text]