Molecular and Genetic Mechanisms of Tumorigenesis in Multiple Endocrine Neoplasia Type-1
Sydney S. Guo and
Mark P. Sawicki
Department of Surgery, West Los Angeles Veterans Affairs Medical
Center and the University of California Los Angeles School of Medicine,
Los Angeles, California 90073
ABSTRACT
Multiple endocrine neoplasia type 1 (MEN1) is a rare but
informative syndrome for endocrine tumorigenesis. Since its
isolation, several groups have begun to determine the role of menin,
the protein product of MEN1, in sporadic endocrine
tumors as well as tumors of the MEN1 syndrome. Mutations of menin have
been reported in more than 400 families and tumors, most of which are
truncating mutations, thus supporting the function of menin as a tumor
suppressor. The exact function of menin is unknown, but overexpression
of menin inhibits proliferation of Ras-transformed NIH3T3
cells. Since menin interacts with proteins from both the TGFß and
AP-1 signaling pathways, perhaps its tumor suppressor function is
related to these key cell growth pathways. In this review we will
discuss the various clinical manifestations of MEN1 syndrome, potential
mechanisms of MEN1 tumorigenesis, and mutations associated with
MEN and sporadic endocrine tumors.
MULTIPLE ENDOCRINE NEOPLASIA type 1 (MEN1, OMIM 131100) is
a rare but informative syndrome for endocrine
tumorigenesis. Nearly a decade after initial mapping of the disease
locus, the responsible gene, called MEN1, was finally cloned
by a large NIH collaborative effort. Since its isolation, several
groups have begun to determine the role of menin, the protein product
of MEN1, in sporadic endocrine tumors as well as tumors of
the MEN1 syndrome. In addition, menin has a number of potential roles
in normal cell function. In this review we will discuss the various
clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1
tumorigenesis, and mutations associated with MEN1 and sporadic
endocrine tumors.
MEN1 CLINICAL MANIFESTATIONS AND TUMOR CHARACTERISTICS
The classic clinical manifestation of MEN1 is the triad of
parathyroid hyperplasia, pancreatic endocrine tumors, and pituitary
adenomas (1, 2). Many MEN1 patients, however, do not have
all three tumors, even at necropsy. A standard definition of MEN1 has
been proposed as an affected individual with at least two of the three
above-mentioned endocrine tumors (3). Familial MEN1
requires the above criteria plus at least one first-degree relative
with one or more of the three defining endocrine tumors. Sporadic MEN1
describes patients with features of MEN1 syndrome but without a family
history of MEN1, indicating de novo germline mutation.
The foremost expression of MEN1 is primary hyperparathyroidism, present
in more than 90% of affected patients (4, 5, 6, 7, 8). The
parathyroid tumors in these patients are often described as
multiglandular hyperplasia, although they may involve the development
of polyclonal and clonal tumors (9, 10). Interestingly,
whereas parathyroid carcinomas account for 1% of sporadic primary
hyperparathyroidism, they are rarely seen in MEN1 patients
(11).
Pancreatic endocrine tumors occur less frequently (
60%) than
parathyroid tumors in MEN1 (12). Most of these tumors are
small, nonfunctional, clinically silent, usually benign, and are
commonly located within or around the pancreas (13, 14).
The most common functional tumors are gastrinomas and insulinomas.
Nonfunctional tumors and insulinomas are located within the
pancreas. Gastrinomas, on the other hand, are often found within
the soft tissue around the pancreas and within the duodenal submucosa,
but not in the mucosa where the gastrin-producing G cells are located.
The stem cell responsible for these tumors is unknown, and gastrinoma
development is therefore difficult to explain (15).
Malignant potential appears to increase with the size of the primary
tumor, although small pancreatic endocrine tumors may also become
malignant (16). Because there are few prospective studies,
it has been difficult to determine whether MEN1-associated pancreatic
endocrine tumors have a better or worse prognosis as compared with
their sporadic counterparts (17).
Of the three classic tumors in MEN1, pituitary adenomas are the least
common and affect approximately 30% of MEN1 patients
(12). Usually these are PRL-secreting microadenomas
(18, 19). Pituitary carcinomas are rare if they occur at
all in MEN1.
When first described by Wermer (2), MEN1 was thought to
include only tumors from the classic triad of endocrine sites. However,
we now know that MEN1 involves other organs, including carcinoid tumors
of the bronchi (20), gastrointestinal tract
(21), and thymus (22), and adrenal cortical
tumors (23, 24), lipomas, angiofibromas, and collagenomas
(25, 26). In most MEN1 families reported, there is
considerable interfamily heterogeneity and variable penetrance
(27, 28, 29). Within families, on the other hand, there is
intrafamily homogeneity as exemplified by MEN1 variants. One variant
named for its origin in Newfoundland, called MEN1-Burin, is associated
with the development of prolactinomas, carcinoids, and
hyperparathyroidism, but rarely pancreatic endocrine tumors (30, 31). Another variant, familial isolated primary
hyperparathyroidism (FIHP), is characterized by the occurrence of
hyperparathyroidism and the absence of pancreatic and pituitary tumors.
While several FIHP families have mutations of MEN1, other
FIHP families have linkage to a different locus on chromosome 1
(32, 33, 34, 35, 36, 37). Factors other than the specific MEN1
mutation may influence disease expression and may account for some of
the phenotype variants. Monozygotic twins, for example, may have
differing phenotypes, indicating that the expression of this disease is
affected by environmental factors as well as genetic background
(38, 39).
IDENTIFICATION OF THE MEN1 GENE
MEN1 is an autosomal dominant inherited syndrome caused by
inactivation of a tumor suppressor gene. The MEN1 gene was
first localized to 11q13 by LOH and finally identified by positional
cloning (see Ref. 3 for detailed review) (Fig. 1
). The impetus to pursue this cloning
strategy was based upon Knudsons two-hit hypothesis, an approach that
was successful in cloning another tumor suppressor, the retinoblastoma
gene (40).

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Figure 1. Positional Cloning of the MEN1 Gene
A chromosome 11 ideogram is shown (left) with a detailed
genetic map encompassing a small region of 11q13 containing the
MEN1 gene. Linkage analysis of many MEN1 families showed
tight linkage to 11q13 polymorphic DNA markers and two recombinants
narrowed the region to the interval depicted with the large gray
bar ( 2 Mb). The MEN1 consensus region was
further refined to the 600-kb region (small gray bar) by
LOH analysis of MEN1 and sporadic endocrine tumors. Large DNA fragments
corresponding to the 600-kb region were isolated (e.g.,
bacterial artificial chromosome BAC137C7) and fully sequenced. Many
candidate genes were isolated, and human peripheral blood leukocyte DNA
from MEN1 patients was systematically analyzed for mutation of the
candidate genes. One of these genes, now called MEN1,
was mutated in most of the families studied. The MEN1
gene exon-intron structure is shown (right) as well as
the direction of transcription (arrow).
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Based upon epidemiological studies, Knudson proposed a two-mutation
model ("two-hit hypothesis") of tumor development in which familial
tumors inherit the first hit or mutation as a germline mutation (Fig. 2
); frequently, the germline mutation is
a point mutation and can be identified by sequencing the germline DNA.
The second hit occurs as a somatic mutation in the predisposed
endocrine cell, which eventually becomes a tumor. This second
mutation may occur either by chromosome loss, chromosome loss with
duplication, mitotic recombination, or another localized event such as
a point mutation. The first three possibilities are the most commonly
identified and are manifested by LOH for polymorphic DNA markers
flanking the MEN1 locus. Therefore, tumor LOH can be thought
of as a marker for a nearby tumor suppressor gene (41). As
a consequence of these two mutations, both alleles of the
MEN1 gene are inactivated in the predisposed endocrine cell.
Sporadic endocrine tumors undergo a similar sequence of events, except
both mutations occur as mitotic events (somatic cell mutation) in the
predisposed endocrine cell.

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Figure 2. Knudson Two-Hit Hypothesis
This diagram illustrates the theoretical molecular genetic
mechanism underlying inactivation of the MEN1 tumor
suppressor gene. In familial cases the first hit is inherited. At the
top left a nuclear family is shown with a single
affected child. Below the parental and child symbols in the pedigree
are allelotypes for two 11q13 polymorphic DNA markers, designated A and
B, flanking the MEN1 gene. Each of these markers has two
possible alleles numbered 1 and 2. The affected child is heterozygous
(A1/A2, B1/B2) for both DNA markers. The normal MEN1
allele is designated "+" whereas the mutated allele is designated
MEN1. For the sake of clarity, only one of the potential
mechanisms for the second hit is shown. In this particular case, the
tumor has undergone chromosome loss as the second hit. The resultant
tumor allelotype is shown (A1/-, B1/-). Southern blot analysis with
the DNA probes A and B demonstrate that while the normal peripheral
blood leukocyte (N) DNA retains a heterozygous (two alleles for each
marker) band pattern for both markers A and B, the tumor (T) DNA shows
a homozygous (one allele for each marker) band pattern. The change to
the homozygous allelotype is called LOH. The lost allele is designated
by the arrow. The sporadic tumor arises by a similar
mechanism except that both hits arise as somatic mutations.
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The initial localization of the MEN1 gene to chromosome 11
was determined by LOH analysis of MEN1 pancreatic endocrine tumors
(Fig. 1
). Insulinoma DNA from two related MEN1 patients was analyzed
with polymorphic DNA probes representing all human chromosomes
(42). These tumors revealed LOH for all informative loci
on chromosome 11, but for very few markers on other chromosomes. This
suggested that these tumors had lost a chromosome that unmasked a
mutated MEN1 gene located on chromosome 11, and genetic
linkage analysis indicated the gene was indeed located near the human
muscle glycogen phosphorylase gene (PYGM) at 11q13.
Subsequent studies in tumors from other MEN1 patients frequently
demonstrated LOH for polymorphic DNA markers located on chromosome 11
near PYGM, suggesting that the MEN1 gene was indeed a tumor
suppressor (43, 44, 45). Sporadic tumors of the type
associated with MEN1 also demonstrated LOH for DNA markers at 11q13
(43, 44, 45, 46, 47, 48, 49, 50). Additional linkage studies (49, 51, 52, 53, 54, 55) refined the MEN1 locus to a smaller 2
centiMorgan [
2-Megabase (Mb) DNA] interval centered on PYGM
(Fig. 1
). All of the MEN1 families reported to date have tight linkage
to the 11q13 locus (42, 49, 51, 52, 53, 54, 55, 56, 57).
Using a positional cloning strategy, the MEN1 gene was
localized to a small genomic interval at 11q13 (49, 58)
and isolated (59) (Fig. 1
). Mutation analysis revealed
that the gene now called MEN1 was frequently, but not
always, mutated in MEN1 families (59). In MEN1-associated
tumors, the mutated MEN1 allele is present in all cells at
birth. Loss of the remaining wild-type allele gives the predisposed
endocrine cell a survival advantage needed for tumor formation. Because
MEN1 patients inherit the first hit, MEN1-associated tumors have an
earlier age of onset and a much higher rate of postoperative recurrence
as compared with their sporadic tumor counterparts. This is consistent
with the classic two-hit hypothesis of tumor suppressors described by
Knudson (40).
EXPRESSION AND FUNCTION OF THE MEN1 GENE
The MEN1 gene spans 9 kb of the genome, and consists of
10 exons. MEN1 encodes menin, a 610-amino acid protein that
is highly conserved (Fig. 3
) among human,
mouse (98%), and rat (97%), and more distantly among zebrafish (75%)
and Drosophila (47%) (60, 61, 62, 63, 64), but there is no
known homolog in the budding yeast Saccharomyces. Most of
the divergence between species is near the carboxy terminus. Database
analysis of menin protein sequence reveals no significant homology to
known consensus protein motifs, but there are 28 putative
phosphorylation sites, two of which are affected by disease-producing
missense mutations. There is also a leucine zipper motif within the
amino terminus, although there are no data supporting dimerization or
DNA binding for menin, suggesting that this motif may not be
biologically relevant (59). Since there are few clues to
menins function by its protein sequence, most of what is known about
its function is derived from in vitro studies.

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Figure 3. Alignment of Menin Protein
The human, mouse, zebrafish, and Drosophila menin
proteins were aligned with ClustalW program
(http://workbench.sdsc.edu/) using the default parameters.
Green areas highlight identically conserved amino acids
between these species, while yellow and
blue areas indicate lesser degrees of conservation.
Missense mutations are indicated by red dots above each
amino acid affected. Open boxes indicate JunD binding
domains. Seventy-one percent of missense mutations occurred on an amino
acid that is identically conserved, while 5% of missense mutations
occurred on amino acids that were not conserved. This is in contrast
with the relatively distant homology between Drosophila
and human MEN1 (34% identical and 47% similar to
human). Zbfsh, Zebrafish.
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Menin is variably expressed in both endocrine and nonendocrine tissues.
In adult human tissues, menin is widely expressed but is highest in
proliferating tissues, such as the uterine endometrium
(65). This association suggests that menin expression may
be cell cycle regulated, and studies of GH4 (rat pituitary) cells
(66) and Chinese hamster ovary (CHO) cells
(65) indeed show that menin expression is modestly
decreased in mid-G1. Analysis of other cell
lines, however, has demonstrated no cell cycle regulation of menin
expression (60, 67). Studies of developmental regulation
of MEN1 have found that mice express menin as early as
embryonic day 7 and later develop a more restricted pattern of
expression (60, 68, 69). Similarly, human fetuses also
express MEN1 early in development (67). A
MEN1 isoform identified in human and mouse is due to an
alternate splice site within exon 2 that lengthens menin by five amino
acids. The biological relevance of this alternate splice variant is
unknown, and no mutations have been mapped to this region.
There is evidence that suggests menin may be regulated, in part, by
nuclear localization. Menin localizes predominantly in the nucleus via
two C-terminal nuclear localization signals (Fig. 4
) (70) but may be found in
the cytoplasm during cell division in HEK 293 (human embryonal kidney)
cells (71). Cytoplasmic localization was also seen in HeLa
and NIH3T3 cells, but this was not cell cycle regulated
(67). In addition to observations in cell lines,
cytoplasmic localization was noted in the developing mouse testes and
developing zebrafish embryo proerythroblasts (63, 69). The
biological significance of this nuclear shuttling is unknown, but other
tumor suppressors, such as von Hippel-Lindau, are regulated in this
fashion (72). All of the MEN1 truncating
mutations lead to loss of one or both nuclear localization signals.
Presumably, this would lead to protein instability or loss of function
by displacing menin out of the nucleus. Interestingly, none of the
missense mutations reported to date alters either nuclear localization
signal (NLS).

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Figure 4. Missense Mutations
Mutation sites and exon lengths were drawn to scale based on the amino
acid sequence of MEN1 (GenBank U93236). Several clusters
of missense mutations can be seen. Some of these directly involved one
of the three JunD interacting regions (amino acids 140, 139242, and
323428). The two nuclear localization signals, however, were spared
(amino acids 479497 and 588608). Diseases produced were represented
using symbols as follows: solid diamond, parathyroid
hyperplasia; arrowhead, neuroendocrine; GI,
star, neuroendocrine, lung; and solid
square, MEN1 syndrome.
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Since all cell lines express menin (67, 68), most
studies have used overexpression of menin to determine its biological
effect on cell growth. In a constitutively activated
Ras-transformed NIH3T3 cell model, high levels of menin
expression reversed the transformed phenotype (73). These
morphological changes were associated with decreased proliferation,
suppression of clonogenicity in soft agar, and inhibition of tumor
growth in nude mice. Menin was overexpressed 7- to 27-fold in this
model, and in vitro growth was suppressed at all levels of
menin expression. Since menin overexpression repressed the effects of
Ras, it would be expected that suppression of menin
expression might increase cell proliferation. However, in a menin
antisense model, partial inhibition of menin expression did not
increase CHO cell proliferation (65).
There is increasing evidence that menin may function in DNA repair or
synthesis. Peripheral blood leukocytes and fibroblasts from MEN1
patients treated with diepoxibutane had an increase in the frequency of
spontaneous chromosomal alterations (74). Similar analyses
of MEN1 lymphocytes revealed an increased frequency of mitoses with
premature centromere division when cells were treated with
diepoxibutane (75, 76). More recently, Ikeo et
al. (65) demonstrated that CHO cells overexpressing
menin had a marked delay in cell cycle progression when exposed to
diepoxibutane. The mechanism by which menin regulates DNA synthesis or
the cellular response to DNA damage is currently unknown.
The molecular mechanism for menins growth suppression is
thought to be mediated, in part, through its interactions with
transcription factors. The first clue came from yeast two-hybrid
protein interaction studies that demonstrated menin binding to JunD
(77). JunD is a member of the Jun family of proteins
(JunD, JunB, c-Jun) that dimerize with themselves or with Fos family
members (c-Fos, FosB, Fra1, Fra2) to form the AP-1 transcriptional
factor. Menin binds to JunD, but not to other members of Jun or Fos,
and represses JunD-mediated transcriptional activation in an in
vitro reporter system. This repression is abrogated by the histone
deacetylase inhibitor trichostatin A, suggesting the importance of DNA
ultrastructure in this mechanism (78). Agarwal et
al. (77) reported three critical regions important
for JunD binding based upon interaction in the yeast-two hybrid system
and glutathione-S-transferase pull-down assays. In contrast,
Gobl et al. (78) suggested primarily a critical
region at the extreme C terminus based upon
glutathione-S-transferase pull-down assays.
The biological function of JunD is not well characterized. While JunD
has significant homology to oncogenic c-Jun, they appear to have
opposing effects on cell growth; overexpression of JunD in
Ras-transformed NIH 3T3 cells inhibits cell proliferation
whereas c-Jun increases cell proliferation (79). Recent
studies of JunD-/- fibroblasts reveal that the absence of JunD may
result in either early senescence (in primary fibroblasts) or increased
proliferation (in immortalized fibroblasts) (80). This
would suggest that the menin-JunD interaction must be studied in the
proper cellular context. Recently, Kaji et al.
(81) have implicated menin in TGFß signaling pathway
through its interaction with Smad3. (SMAD = vertebrate
homologs to C. elegans Sma and Drosophila Madproteins. Because it is known that JunD interacts with Smad3
(82), it has been proposed by others that TGFß may exert
its function, in part, through Smad3, JunD, and menin
(81).
An exciting recent development is the creation of a MEN1
knockout mouse through cre/lox recombination that will
provide a useful in vivo model in which to study
MEN1 function (83).
MEN1-/- mice had an embryonic lethal
phenotype, while MEN1+/- mice
developed tumors of the endocrine pancreas (predominantly ß-cells),
parathyroid, and pituitary. LOH analysis revealed that the insulinomas,
but not hyperplastic islets, have lost the remaining wild-type allele,
thus recapitulating the genetic mechanism seen in human disease. This
also suggests that menin has a dosage effect on islet growth
regulation. Notably, no gastrinomas were observed. This model, together
with the JunD knockout mouse (80), should greatly
accelerate our understanding of MEN1 function. In
particular, the dependence of JunD in MEN1 tumorigenesis
could be explored by crossing these two knockout mouse strains. It
would be expected that if JunD is necessary for menin function, then
the double knockout mice should not spontaneously develop tumors.
MEN1 MUTATIONS
Since the cloning of MEN1, more than 400 mutations have
been reported in families and sporadic tumors. We reviewed a total of
326 MEN1, 7 FIHP, and 92 sporadic tumor mutations, compiled
from 51 distinct studies (20, 27, 32, 33, 34, 35, 36, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127). Many
mutations were reported more than once in apparently unrelated patients
(range, 213 times), and the number of unique mutations is 294. There
were 169 deletions (40%), 85 missense mutations (20%), 82 nonsense
mutations (19%), 56 insertions (13%), 29 splice site defects (7%),
and 4 combined deletion/insertion (1%) mutations. Of the 294 unique
mutations, 220 of these are truncating mutations resulting from
frameshift (deletions, insertions, deletion/insertions, or splice-site
defects) and nonsense mutations. These truncating mutations predict a
loss-of-function of menin and therefore support menins role as a
tumor suppressor.
Of the MEN1 missense mutations reported in the literature,
68% occurred on an amino acid that is identical among human, mouse,
zebrafish, and Drosophila (Fig. 3
). A further 27% of
missense mutations occurred on amino acids that are not identical among
these species but belonged to the same polar/nonpolar side-chain group.
Only 5% of missense mutations occurred on amino acids that were not
conserved. This is remarkable given the relatively distant homology for
the fly (34% identical and 47% similar to human).
Currently, there are five known functional domains of menin (Fig. 4
):
three JunD-interacting domains at codons 140, 139242, and 323428,
and two nuclear localization signals at codons 479497 and 588608
(70, 77). Further analysis revealed that there are three
clusters of missense mutations that occurred in the three JunD-binding
sites (43 of 74 unique missense mutations, or 58%), but several other
clusters were scattered outside of all the known functional domains
(accounting for 42% of total unique missense mutations). The clusters
outside of the JunD binding domains may be important for Smad3 binding
or may argue for the existence of as yet unidentified binding partners
of menin. It is also conceivable that they may disrupt the
three-dimensional conformation and indirectly affect menins affinity
for JunD or the cellular localization mechanism. Another possibility is
that these mutations may alter the protein degradation mechanism,
leading to abnormal protein half-life and consequently, loss of
function.
MEN1 mutations occur not only in MEN1 patients (both
familial and sporadic), but also in a significant percentage of
associated sporadic endocrine tumors (Fig. 5
). Interestingly, the profile of tumors
associated with MEN1 differs from the profile of sporadic tumors in
which MEN1 has been implicated in the tumorigenesis. For
example, approximately 30% of MEN1 patients are affected by pituitary
tumors. However, MEN1 mutation is almost never seen in the
sporadic form of pituitary tumors (2 of 195, 1%). Among sporadic
pancreatic endocrine tumors, the frequency of MEN1 mutation
differs between the types of tumor. For example, the frequency of
MEN1 mutation in sporadic gastrinomas is 37%, in contrast
to the 15% mutation rate in nongastrinoma sporadic pancreatic
endocrine tumors. Moreover, even though a recent report found no
MEN1 mutation in 27 sporadic insulinomas examined
(120), only insulinomas were found in the recently
reported MEN1 knockout mouse model (see above) (83).
Therefore, the role of MEN1 may be different in familial and
sporadic tumors.

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Figure 5. MEN1 Mutation Frequency in Sporadic Tumors of
Different Tissues
Mutations were reviewed and categorized according to the site of the
sporadic tumor. These numbers were then expressed as a fraction of the
total number of each disease type analyzed in each report. Sporadic
neuroendocrine tumor (NET)-Pulmonary, 35% (6 of 17); sporadic NET-GI
tract (including pancreatic endocrine tumors as well as carcinoids of
GI tract), 23% (45 of 196); sporadic parathyroid adenoma, 13.4% (36
of 267); sporadic angiofibromas, 10.5% (2 of 19); sporadic adrenal
tumors, 7.1% (1 of 14); sporadic pituitary adenomas, 1% (2 of 195)
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Although there is not a consistent phenotype-genotype correlation
in familial MEN1, there is such an association in sporadic gastrinomas.
Primary pancreatic or lymph node sporadic gastrinomas exhibit mutations
in exon 2 much more frequently than duodenal sporadic gastrinomas
(128). Small (<1 cm) primary tumors were also less likely
to have a mutation involving exon 2 of MEN1. However, there
was no genotype-phenotype correlation with regard to postoperative
disease-free status and overall patient outcome.
Fifty-five MEN1 mutations have been reported repeatedly in
the literature. Only mutations that were reported greater than three
times in patients who have no apparent relationship with one another
are listed in Table 1
(total, 17). The
most frequently repeated mutation, 359del4, occurred in 13 presumably
unrelated families and suggests a mutation "hot spot." However, it
is possible that some of these patients are related, as demonstrated by
a study (129) revealing founders effect for two repeat
mutations (416delC and 512delC) described in families that were
apparently unrelated by both family history and geographical origin.
Although this may be the case, analysis of clinical diseases reported
with these repeat mutations suggests there is not an emerging
phenotype-genotype correlation amongst MEN1 families.
Thirteen polymorphisms have been reported in the literature. Two
polymorphisms altered the amino acid sequence of menin
(Arg171Gln and Ala541Thr),
and both involved amino acid substitutions between different polar
side-chain groups. Interestingly, Arg171Gln
occurs in the middle of the missense mutation cluster between amino
acids 126184. Missense mutation at almost every other amino acid in
this area causes disease. Similarly, Ala541Thr
also occurs in the middle of a smaller cluster of disease-producing
missense mutations. Of note, there were two reports that categorized
the Ala541Thr polymorphism as a disease-producing
mutation, leading to a parathyroid adenoma and a neuroendocrine tumor
of the foregut, respectively (116, 121). Contrastingly,
G8949A was first reported to be a benign polymorphism by Bassett
et al. (86) but later reclassified by several
groups to be a disease-causing mutation (96, 99, 102, 111).
In familial MEN1 patients, germline mutation of MEN1 was
found in 271 of 351 probands studied (77%). Less frequently,
MEN1 germline mutation was found in 55 of 86 cases (64%) of
sporadic MEN1 patients. Thus, in total, 326 mutations (271 + 55) were
reported in MEN1 patients. Most studies used one of four methods in the
detection of mutations: dideoxy fingerprinting, heteroduplex analysis,
single strand conformation polymorphism, or direct sequencing of
selected regions. Short of sequencing the entire gene and the
surrounding areas, none of these methods is completely sensitive.
Additionally, mutations in the untranslated regions or regulatory
regions may be responsible for the cases where MEN1
mutations have not been detected. Although all MEN1 families tested to
date have tight linkage to 11q13, the presence of another tumor
suppressor at 11q13 is also a possibility (130). One
family with a large germline deletion of MEN1 that would
escape detection by PCR-based methods has been reported
(103). The existence of phenocopies should also be
considered, especially in light of the high frequency of sporadic
parathyroid and pituitary adenomas (85). This point is
highlighted in sporadic MEN1 patients where the lack of family history
makes this diagnosis more susceptible to phenocopies and is reflected
in the lower rate of MEN1 mutation in sporadic
vs. familial MEN1. Lastly, even when genetic change is
identified in MEN1 families, the general slow growth of these tumors
and the lack of adequate treatment modalities available make the issue
of routine genetic testing, at best, unresolved.
The field eagerly awaits the discovery of a functional assay for menin
activity. This assay could not only elucidate mechanisms of menin
inactivation other than genetic mutation, but could also lead to the
rational design of treatment modalities for both MEN1 and the sporadic
endocrine tumors.
ACKNOWLEDGMENTS
We thank Dr. Edward Passaro, Jr., for intellectual guidance and
support. We also thank Dr. Greg Brent for invaluable critique of the
manuscript, and Alan Shimoide and Karen Duff for technical support.
FOOTNOTES
Address requests for reprints to: Mark P. Sawicki, M.D., Department of Surgery, 11301 Wilshire Boulevard, Los Angeles, California. E-mail:
msawicki{at}ucla.edu
{hd1}Note Added in Proof
{smtexf}Menin was recently found to interact with and antagonize the
NF-kappaB proteins (131 ).
Abbreviations: CHO, Chinese hamster ovary; FIHP, familial
isolated primary hyperparathyroidism; MEN, multiple endocrine
neoplasia; Mb, megabase; NLS, nuclear location signal; SMAD, vertebrate
homologs to C. elegans Sma and DrosphilaMadproteins.
Received for publication August 31, 2000.
Accepted for publication July 10, 2001.
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