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Original Studies |
Department of Medicine, University of Illinois (M.R.G., S.F.M., R.D.K., L.A.F.), Chicago, Illinois 60612; the Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California (T.R.P., S.M.), Los Angeles, California 90048; the Department of Medicine, Federal University of Rio de Janeiro (M.R.G., K.N.U., M.V.), Rio de Janeiro, Brazil; and the Department of Neurosurgery, Cook County Hospital and Rush Medical College (R.P.G.), Chicago, Illinois 60612
Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Department of Medicine (M/C 787), University of Illinois, 840 South Wood, Chicago, Illinois 60612. E-mail: frohman{at}uic.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Only a small number of somatotropinomas occur with a familial aggregation, either as isolated acromegaly/gigantism or as a component of a multiple endocrine neoplasia complex, including the Carney complex and the Wermer syndrome [multiple endocrine neoplasia type 1 (MEN-1)]. The Carney complex exhibits an autosomal dominant phenotype characterized by myxomas, spotty skin pigmentation, and endocrine tumors (testicular, adrenal, and pituitary) (7, 8), in which up to 21% of patients have GH-secreting pituitary tumors (9). The Carney complex is genetically heterogeneous (10), with one of the responsible genes linked to chromosome 2p16 (11). MEN-1, in contrast, is an autosomal dominant predisposition to hyperplasia/tumor of the parathyroid glands, endocrine pancreas, and anterior pituitary. Forty-five percent of MEN-1 patients develop pituitary adenomas, of which 10% are somatotropinomas and 60% are prolactinomas (12).
In 1988, Larsson et al. (13) mapped the MEN-1 locus to chromosome 11q13, and 9 yr later, Chandrasekharappa et al. (14) cloned the MEN-1 gene, which encodes a 610-amino acid protein (menin) of unknown function. Agarwal et al. (15) reported a high prevalence of germline mutations in the coding region of the MEN-1 gene in 47 members of 50 MEN-1 families. This finding, coupled with the fact that loss of heterozygosity (LOH) in chromosome 11q13 occurs in pancreatic (13), parathyroid (16), and pituitary tumors (17) of MEN-1 patients, suggests that this syndrome is initiated by the complete inactivation of a tumor suppressor gene (MEN-1). This is in accord with Knudson’s "two-hit" theory, which states that initiation of neoplasia requires independent inactivation events in each copy of the tumor suppressor gene; the first hit is an inherited allelic germline mutation, and the second is a somatic deletion resulting in LOH (18).
Isolated somatotropinomas are an extremely rare subset of familial
pituitary tumors. This disease is defined as the occurrence of at least
2 cases of acromegaly or gigantism in a family that does not exhibit a
multiple endocrine neoplasia syndrome (Carney complex or MEN-1). Only
42 cases of isolated familial acromegaly/gigantism occurring in 18
families have been reported in the literature since the biochemical
diagnosis of GH excess became available (Table 1
). The pattern of inheritance raises the
possibility of multiple genetic defects. In 1997, Yamada et
al. (19) reported specific LOH on chromosome 11q13 in pituitary
adenomas of 2 brothers with gigantism, suggesting that familial
acromegaly/gigantism may be a phenotypic variant of the MEN-1 syndrome.
In the present study, we sought to explore this possibility by
investigating LOH at 11q13, MEN-1 germline mutations, and MEN-1 gene
expression in 2 unrelated kindreds with familial
acromegaly/gigantism.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Family A, of Mexican origin, is composed of four siblings, three
of whom are affected (Fig. 1, top
panel). The index case, 2A, was a 23-yr-old man who sought medical
help because of headaches, decreased vision, and progressively
enlarging hands and feet. He appeared acromegalic, with a height of 173
cm, and the diagnosis was confirmed by elevated serum GH and
insulin-like growth factor I (IGF-I) levels (Table 2). Magnetic resonance imaging (MRI)
revealed a macroadenoma with suprasellar extension. He underwent
surgical resections in June 1993 (craniotomy) and July 1994
(transsphenoidal), followed by radiotherapy. In 1994, the 21-yr-old
second brother (3A) was also suspected of acromegaly when he
accompanied his brother (2A) to the hospital for a clinic visit.
Subject 3A presented with decreased vision and had physical attributes
characteristic of acromegaly (height, 165 cm). His laboratory results
confirmed the diagnosis (Table 2). MRI revealed a macroadenoma with
suprasellar extension, which was removed in January 1995 by
transsphenoidal surgery, followed by pituitary irradiation. The
19-yr-old third brother (4A) was also investigated because of physical
stigmata of acromegaly. He complained of headaches and gradually
enlarging feet (height, 175 cm). A laboratory diagnosis of acromegaly
was made (Table 2); however, the patient declined further evaluation or
treatment. GH and IGF-I levels of the unaffected parents and sister are
presented in Table 2 for comparison. Plasma GHRH levels were normal in
all subjects (data not shown). There was no history of consanguinity,
and the past medical history and laboratory results excluded MEN-1 and
the Carney complex in all affected and unaffected screened
subjects.
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Family B, of Brazilian origin, consisted of 13 siblings, 5 of
whom are affected (Fig. 1
, lower panel). The index case (4B)
presented at 24 yr of age with galactorrhea, headaches, and
progressively enlarging hands and feet that had developed over the
previous 4 yr. She appeared acromegalic, with a height of 165 cm and a
weight of 75.5 kg, and exhibited hyperhydrosis and left temporal
hemianopsia. Elevated basal GH levels and lack of GH suppression by
glucose administration confirmed the diagnosis (Table 3). The MRI revealed a macroadenoma with
infra- and suprasellar extensions. Transsphenoidal surgery was
performed in June 1995, followed by radiotherapy. During the clinical
history, she reported that a brother (2B) and a sister (10B) were tall
in stature. Subject 2B, a 29-yr-old man (height of 224 cm), was
diagnosed at 17 yr of age and had subsequently undergone two frontal
craniotomies and radiotherapy. Subject 10B, a 15-yr-old female,
presented with headaches and primary amenorrhea. Her height was 185 cm,
and her weight was 100 kg. Serum basal GH was elevated and was not
suppressed by oral glucose (Table 3). The computed tomography scan
showed a macroadenoma with suprasellar expansion. Transsphenoidal
surgery was performed in August 1995, followed by radiotherapy.
Subsequent clinical and laboratory screening of the asymptomatic family
members (Table 3) revealed that subjects 11B and 12B also had evidence
of GH hypersecretion. Subject 11B, a 17-yr-old male, with a height of
172 cm and a weight of 57.5 kg, had an elevated serum basal GH value
that was not suppressed during an oral glucose tolerance test (Table 3). The computed tomography scan revealed a microadenoma. Subject 12B,
a 13-yr-old female, with a height of 164 cm and a weight of 53 kg, had
elevated basal GH and IGF-I levels, and serum GH levels were not
suppressed by oral glucose administration (Table 3). A MRI subsequently
revealed a 4.0 x 2.8 x 2.4-cm pituitary macroadenoma with
suprasellar extension (Fig. 2),
confirming the diagnosis of a GH-secreting tumor. Also of interest is
subject 8B, who died at the age of 16 yr with a clinical history
suggestive of pituitary apoplexy. In addition, the father’s brother
was reported to have "coarse" features and died at the age of 18 yr
from a "brain tumor". Subject 9B died at 2 yr of age from an
unrelated condition. There was no history of consanguinity, and the
past medical history and laboratory results excluded MEN-1 and the
Carney complex in all affected and unaffected screened subjects.
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Paraffin tumor blocks were sectioned (5 µm) and stained with hematoxylin-eosin or subjected to immunocytochemistry for GH and PRL using the standard avidin-biotin-peroxidase complex technique. The primary antibodies used in the reaction have been previously characterized [GH, 1:5000 (20); PRL, 1:5000 (NIH)].
Analysis of LOH on chromosome 11q13
The study protocol was approved by the institutional review board of the University of Illinois at Chicago with the informed consent of all subjects. Pituitary adenoma tissue was obtained from paraffin-embedded blocks (patients 2A, 3A, 2B, 4B, and 10B). Fifteen sections (5 µm) were deparaffinized and incubated with 100–300 µL digestion buffer containing 50 mmol/L Tris-HCl (pH 8.5), 1 mmol/L ethylenediamine tetraacetate, 0.5% Tween-20 (Sigma Chemical Co., St. Louis, MO), and 0.1–0.2 mg/mL proteinase K (Life Technologies, Grand Island, NY). Samples were incubated at 37 or 55 C for 120 h. After centrifugation, the supernatant was transferred to a fresh tube and proteinase K heat inactivated (95 C, 8 min). Organic extraction (phenol-chloroform) was necessary to obtain PCR products from tumor sample 10B.
Peripheral blood samples were collected from all eight patients, their parents, and unaffected siblings. DNA was extracted from leukocytes with DNAzol (Life Technologies). The concentration of leukocyte DNA was determined spectrophotometrically.
Tumor DNA (3 µL) or leukocyte DNA (500 ng) was amplified using
primers specific for microsatellite markers, PYGM (CA GA) and D11S527
(Research Genetics, Inc., Huntsville, AL), both of which
are on chromosome 11q13 and closely linked to the MEN-1 gene. The
repeat CA GA is located within the muscle glycogen phosphorylase gene
(PYGM), which is centromeric to the MEN-1 gene, whereas D11S527 is
telomeric. The reverse primer of each oligonucleotide pair was end
labeled with [
-32P]ATP using the 5' DNA Terminus
Labeling System kit (Life Technologies). The PCR reaction
mixture (20 µL) contained 1 x PCR buffer (Perkin Elmer, Norwalk, CT), 1.0 mmol/L MgCl2, 0.2 mmol/L
deoxy (d)-NTPs (Boehringer Mannheim, Indianapolis, IN), 0.25 µmol/L
primers, and 1.5 U AmpliTaq (Perkin Elmer). A "hot
start" was performed at 95 C for 90 s, and each of the 39
subsequent cycles consisted of denaturation at 94 C for 40 s,
annealing at 62 C for 40 s, and extension at 72 C for 60 s,
followed by a final extension at 72 C for 5 min. Leukocyte and tumor
DNA products were electrophoresed in a 6% polyacrylamide-8.3 mol/L
urea gel. The PCR products were visualized by PhosphorImager
(Molecular Dynamics, Inc., Sunnyvale, CA) or
autoradiography. The predicted sizes of PYGM and D11S527 alleles were
156–190 and 142–166 bp, respectively; the markers were considered
informative if leukocyte DNA showed heterozygosity. The intensity of
the alleles was measured by image analysis of the PhosphorImager
(ImageQuant, Molecular Dynamics, Inc., Sunnyvale, CA). A
greater than 50% decrease or the absence of one of the expected PCR
products in the tumor sample compared with the leukocyte sample was
interpreted as LOH.
MEN-1 gene sequencing
Tumor DNA was obtained from 15–20 sections (7 µm) from paraffin-embedded tissue. Sections were deparaffinized and treated with 0.5 mg/mL proteinase K (Ambion, Inc., Austin, TX) in 200 µL 1 x Perkin Elmer PCR buffer without MgCl2 (37 C). The proteinase K was heat inactivated at 95 C for 5 min, and the DNA was further purified using the QIAamp tissue kit (Qiagen, Santa Clarita, CA) and eluted with 100 µL 0.5 x kit buffer (AE).
Leukocyte DNA of one affected and one unaffected member of each family
(3A, 1A, 4B, and 1B) and tumor DNA from subjects 3A and 4B were used
for sequencing. Nine coding exons and 17 splice junctions of the MEN-1
gene were amplified by PCR in 50-µL reactions containing 150 ng
leukocyte DNA or 5 µL tumor DNA, 1 x PCR buffer with 1.5 mmol/L
MgCl2, 0.2 mmol/L dNTPs, 10 pmol primer, and 2.5 U AmpliTaq
Gold (Perkin Elmer). Dimethylsulfoxide (10%) was included
for the amplification of exon 10. PCR conditions were 94 C for 10 min,
followed by 40 cycles of 94 C for 30 s, 55–60 C for 30 s,
and 72 C for 1–2 min. The annealing temperature depended on primers,
whereas the extension time varied with product length. PCR products are
shown in Table 4 with their associated
exon coordinates.
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-33P]dideoxy-NTP
ThermoSequenase kit (Amersham, Arlington Heights, IL). Reactions were
electrophoresed in 6% acrylamide-7 mol/L urea gels and
autoradiographed. Dimethylsulfoxide (10%) was included for exon 2
(2652R) and exon 10 sequence reactions. The genomic DNA coordinates for
the primers used in the sequencing reactions are provided in Table 4.
Sequencing of the MEN-1 gene from tumor DNA required PCR amplification
of shorter sequence motifs, also shown in Table 4. MEN-1 gene expression
A small fragment of tumor from patient 3A was collected at surgery and stored at -70 C. Total ribonucleic acid (RNA) was extracted according to the Tri Reagent protocol (Molecular Research Center, Inc., Cincinnati, OH) with the exception that the aqueous phase was further purified by extraction with phenol-chloroform-isoamyl alcohol (25:24:1; pH 5.2; Fisher Scientific International, Inc., Pittsburgh, PA). RNA was resuspended in 10 mmol/L Tris-HCl (pH 7.6) and 1 mmol/L ethylenediamine tetraacetate, and RNA concentration was determined spectrophotometrically.
Total RNA (1 µg) was reverse transcribed using the Superscript Preamplification System for First Strand Complementary DNA (cDNA) Synthesis Protocol (Life Technologies), primed with random hexamers (0.2 µg). One tenth (2 µL) of the RT reaction was amplified by PCR in a final volume of 50 µL that included 1 x PCR buffer (Perkin Elmer), 1.5 mmol/L MgCl2, 0.2 mmol/L dNTPs (Boehringer Mannheim), 0.2 µmol/L primers, and 2.5 U AmpliTaq (Perkin Elmer). The PCR conditions were denaturation at 95 C for 3 min, followed by 40 cycles of 94 C for 1 min, 62 C for 1 min, 72 C for 2 min, and a final extension at 72 C for 15 min. A 25-µL aliquot of the PCR product was analyzed by gel electrophoresis using a 1.5% agarose gel containing ethidium bromide (0.5 µg/mL). The primers amplified a 382-bp product spanning nucleotides 252–633 of the MEN-1 cDNA (GenBank accession no. U93236).
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Results |
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Immunocytochemistry revealed that all tumors were strongly positive for GH (>90% of tumor cells). Tumors 2A, 3A, 2B, and 4B did not exhibit immunoreactivity for PRL, whereas tumor 10B showed scattered PRL-positive cells (<3% of cells).
Analysis of LOH on chromosome 11q13
The microsatellite markers, PYGM and D11S527, were informative in
both families. LOH on 11q13 was observed using PYGM in all five tumors
studied (Figs. 3 and 4). In addition, all adenomas showed LOH at 11q13
using the D11S527 (data not shown), demonstrating the extent of
chromosomal loss. The chromosomal segment that was deleted (transmitted
by the mother in both families) is presumed to contain the wild-type
copy of the tumor suppressor gene. Consequently, the germline mutation
that predisposed these individuals to neoplasia was transmitted
paternally (allele C; Figs. 3 and 4). Individual 13B, a 10-yr-old female,
has inherited the putative mutant chromosome and is, therefore, at risk
of developing a pituitary adenoma.
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Sequencing of PCR-amplified constitutional DNA from an affected individual in each family (3A and 4B) revealed no germline mutations within the nine coding exons and the exon-intron boundaries of the MEN-1 gene. However, leukocyte DNA of two unaffected subjects had a sequence change in intron 7. Subject 1A was homozygous with an A to G change at position 6276, whereas 1B was heterozygous at the same position (6276 A/G). These changes would not modify the splicing process and are presumed to be benign polymorphisms. In addition, no somatic mutation of the MEN-1 gene was detected in the pituitary adenoma of subject 3A, whereas sequencing of tumor DNA from subject 4B was not successful.
MEN-1 gene expression
RNA from tumor 3A and a normal pituitary (autopsy) was subjected
to RT-PCR using primers from exons 2 and 3 of the MEN-1 gene. PCR
products from both the tumor and normal RNA showed a 382-bp band (Fig. 5), which corresponded to that predicted
from the MEN-1 cDNA sequence (GenBank accession no. U93236). These
results demonstrate that the MEN-1 gene is effectively transcribed in
the pituitary adenoma.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Because of the limited size of each kindred and the number of affected subjects in the present study, it was not possible to conclusively establish the mode of transmission. We, therefore, initially considered the possibility of an activating mutation of the GHRH receptor, as hyperactivity of the GHRH signal transduction system can lead to somatotrope hyperplasia and/or adenoma formation (21). However, sequencing of leukocyte DNA and tumor cDNA from members of family A failed to reveal mutations in the GHRH receptor gene (data not shown).
The possibility of a loss of a tumor suppressor gene was considered by comparing the polymorphic markers, PYGM and D11S527, in leukocyte and tumor DNA. Both revealed LOH of 11q13 in all pituitary tumors tested, suggesting that a tumor suppressor gene important for somatotrope tumor formation is present at this locus. Despite the phenotypic dissimilarities between isolated familial acromegaly/gigantism and MEN-1 syndrome, the MEN-1 gene was considered a candidate because it has been shown to contain inactivating germline mutations in the majority of patients with pituitary tumors associated with the MEN-1 syndrome (14, 15). However, sequencing of the coding regions and the intron/exon boundaries of the MEN-1 gene showed no germline mutation in either family despite the presence of LOH at the 11q13 locus. These results are consistent with the recent report by Tanaka et al. (22) that detected no germline mutations within the coding region of the MEN-1 gene in two kindreds with familial acromegaly.
We also explored the possibility that the progression of neoplasia in each kindred could be due to a secondary somatic mutation in the MEN-1 gene. To investigate this possibility, tumor DNA (3A) was sequenced, but was found to be normal. This is in contrast to the report by Tanaka et al. (22) of a nonsense somatic mutation in the MEN-1 gene in one of two brothers with somatotropinomas that exhibited LOH on 11q13. We did not perform complete intron and promoter region sequencing of the MEN-1 gene or investigate methylation-dependent gene silencing (23). Therefore, we cannot be certain that the level of MEN-1 gene expression is normal in these families. However, the integrity of the MEN-1 gene in this subject (3A) is supported by our observation that the tumor expressed the MEN-1 gene, as assessed by RT-PCR. Taken together, these observations implicate a tumor suppressor gene located within chromosome 11q13 that is independent of MEN-1.
LOH of 11q13 in sporadic pituitary adenomas is not associated with genetic mutations (24, 25) or abnormal expression of the MEN-1 gene (25). When combining the results of three published studies (24, 25, 26), it appears that 11q13 allelic loss occurs more frequently in somatotropinomas (19%; 8 of 43) than in corticotropinomas (12%; 3 of 25), nonfunctioning or gonadotropinomas (11%; 8 of 72), prolactinomas (10%; 3 of 30), or thyrotropinomas (0 of 2). A recent report by Farrell et al. (27) suggests that the frequency of LOH within 11q13 in sporadic GH-producing tumors is as high as 38%. Mutational analysis of 13 GH-secreting tumors with allelic loss (24, 25, 27) revealed only 1 with an inactivating mutation of the MEN-1 gene (24). These findings together with the present report strongly suggest that a novel (tissue-specific?) tumor suppressor gene(s) is expressed in the pituitary that is essential for the modulation of somatotrope proliferation.
The very high penetrance occurring at an early age in our subjects along with the fact that the majority (63%) of reported cases of familial somatotropinomas are diagnosed before the age of 30 yr imply that the loss of this putative tumor suppressor gene, located within 11q13, is the initiating event in somatotrope tumorigenesis. Furthermore, genetic analysis of sporadic pituitary adenomas has revealed a higher frequency of invasive compared to noninvasive tumors associated with a single allelic loss at 11q13 (5). This observation coupled with the fact that the adenomas in this report were aggressive suggest that this tumor suppressor gene is not only the initiator of tumorigenesis, but exerts an effect on neoplastic progression. Genes already identified within the 11q13 locus code for a variety of proteins that have important roles in cell cycle regulation and intracellular signaling, including BclI, galanin, vascular endothelial growth factor, B56 ß-subunit of protein phosphatase 2A, fas-associating protein with death domain, ß-adrenergic receptor kinase, phospholipase C, and fibroblast growth factor-4 [which has been associated with invasive prolactinomas (28)]. Which, if any, of these genes are involved in neoplastic transformation of the somatotrope is still unclear.
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Acknowledgments |
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Footnotes |
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Received July 28, 1998.
Revised September 18, 1998.
Accepted September 30, 1998.
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References |
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-subunit- and
thyrotrophin-cosecreting pituitary adenoma in familial setting of
pituitary tumour. Acta Endocrinol (Copenh). 129:516–518.This article has been cited by other articles:
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  C. A. Leontiou, M. Gueorguiev, J. van der Spuy, R. Quinton, F. Lolli, S. Hassan, H. S. Chahal, S. C. Igreja, S. Jordan, J. Rowe, et al. The Role of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in Familial and Sporadic Pituitary Adenomas J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2390 - 2401. [Abstract] [Full Text] [PDF]
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A. F. Daly, M.-L. Jaffrain-Rea, A. Ciccarelli, H. Valdes-Socin, V. Rohmer, G. Tamburrano, C. Borson-Chazot, B. Estour, E. Ciccarelli, T. Brue, et al. Clinical Characterization of Familial Isolated Pituitary Adenomas J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3316 - 3323. [Abstract] [Full Text] [PDF]
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B. S. Soares, K. Eguchi, and L. A. Frohman Tumor Deletion Mapping on Chromosome 11q13 in Eight Families with Isolated Familial Somatotropinoma and in 15 Sporadic Somatotropinomas J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6580 - 6587. [Abstract] [Full Text] [PDF]
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 A Cebrian, S Ruiz-Llorente, A Cascon, M Pollan, J J Diez, A Pico, D Telleria, J Benitez, and M Robledo Mutational and gross deletion study of the MEN1 gene and correlation with clinical features in Spanish patients J. Med. Genet., May 1, 2003; 40(5): e72 - 72. [Full Text] [PDF]
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E. J. Lee, T. J. Kotlar, I. Ciric, M. K. Lee, S. K. Lim, H. C. Lee, K. B. Huh, K. E. Mayo, and J. L. Jameson Absence of Constitutively Activating Mutations in the GHRH Receptor in GH-Producing Pituitary Tumors J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3989 - 3995. [Abstract] [Full Text] [PDF]
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B. H. Jorge, S. K. Agarwal, V. S. Lando, R. Salvatori, R. R. Barbero, N. Abelin, M. A. Levine, S. J. Marx, and S. P. A. Toledo Study of the Multiple Endocrine Neoplasia Type 1, Growth Hormone-Releasing Hormone Receptor, Gs{{alpha}}, and Gi2{{alpha}} Genes in Isolated Familial Acromegaly J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 542 - 544. [Abstract] [Full Text]
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C. A. Stratakis and L. S. Kirschner Isolated Familial Somatotropinomas: Does the Disease Map to 11q13 or to 2p16? J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4920 - 4924. [Full Text]
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T. Abe, K. Yoshimoto, M. Taniyama, K. Hanakawa, H. Izumiyama, M. Itakura, and K. Matsumoto An Unusual Kindred of the Multiple Endocrine Neoplasia Type 1 (MEN1) in Japanese J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1327 - 1330. [Full Text]
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M. R. Gadelha, K. N. Une, K. Rohde, M. Vaisman, R. D. Kineman, and L. A. Frohman Isolated Familial Somatotropinomas: Establishment of Linkage to Chromosome 11q13.1-11q13.3 and Evidence for a Potential Second Locus at Chromosome 2p16-12 J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 707 - 714. [Abstract] [Full Text]
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