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Original Studies |
Department of Medicine, University of Illinois at Chicago (M.R.G., R.D.K., L.A.F.), Chicago, Illinois 60612; the Division of Endocrinology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro (M.R.G., K.N.U., M.V.), Rio de Janeiro, Brazil 21949-590; and the Department of Bioinformatics, Max Delbrück Center for Molecular Medicine (K.R.), Berlin, Germany
Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Department of Medicine (M/C 787), University of Illinois at Chicago, 840 South Wood, Chicago, Illinois 60612.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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= 0.0. As somatotropinomas are the predominant
pituitary tumor subtype associated with CNC and arise before 30 yr of
age, which is strikingly similar to the age at diagnosis for IFS, we
explored the possibility that the putative CNC genes might also
contribute to the pathogenesis of IFS. Although the genetic defect
responsible for the complex is unknown, CNC has been mapped by linkage
analysis to chromosomes 2p15–16 and 17q23–24 in different kindreds.
Two-point LOD scores less than -2.0 were obtained using marker
D17S949 from chromosome 17q23–24, excluding linkage.
However, LOD scores of 2.5 were obtained for markers within 2p16–12;
therefore, linkage of IFS to chromosome 2p cannot be excluded. This
report establishes linkage of the tumor suppressor gene involved in the
pathogenesis of IFS to chromosome 11q13.1–13.3 and identifies a
potential second locus at chromosome 2p16–12. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Carney complex exhibits an autosomal dominant transmission pattern (5, 6) and is characterized by spotty mucocutaneous pigmentation; skin, cardiac, and breast myxomas; schwannomas; ductal adenomas of the breast; and endocrine alterations (7, 8, 9). Endocrine abnormalities associated with CNC include primary pigmented nodular adrenocortical disease, causing ACTH-independent Cushing’s syndrome, and pituitary, thyroid, testicular, and ovarian tumors. Somatotropinomas, the most frequent pituitary adenoma subtype, are present in 10–21% of the patients with CNC, and the onset of GH hypersecretion occurs between 11–27 yr (7, 10, 11, 12). Although the genetic defect responsible for the complex is unknown, CNC has been mapped by linkage analysis to chromosome 2p15–16 in 11 families (13) and to 17q23–24 (14) in 4 families.
IFS is defined as the occurrence of at least 2 cases of acromegaly or
gigantism in a family that does not exhibit any other manifestations of
MEN-1 or CNC. Sixty-one cases in 25 families with confirmed GH
hypersecretion have been reported in the literature, with 70% of cases
diagnosed before the age of 30 yr (15, 16, 17). Analysis of these families
suggests that IFS is inherited as an autosomal dominant disease with
incomplete penetrance. However, the genetic defect responsible for this
rare disease is unknown. We and others have excluded the GHRH receptor
and Gs
as IFS candidate genes (16, 18, 19).
The MEN-1 gene has also been considered a candidate gene for
IFS based on a report by Yamada et al. (20), who described 2
brothers with somatotropinomas that exhibited loss of heterozygosity
(LOH) at 11q13, a genetic alteration typical of MEN-1-associated
tumors. In a recent report we also demonstrated LOH at chromosome 11q13
in all somatotropinomas from 2 IFS families (18). However, sequencing
of the coding region and exon-intron boundaries of MEN-1 in
both families revealed no germline mutations, and detection of
MEN-1 messenger ribonucleic acid (mRNA) indicated the
absence of mutations or hypermethylation in the regulatory regions of
MEN-1 (18) (unpublished data). These observations are
supported by reports from 3 independent laboratories that found no
MEN-1 germline mutations in 10 IFS families (16, 21, 22).
Taken together, these results suggest that a tumor suppressor gene
located at 11q13, distinct from MEN-1, is involved in the
pathogenesis of IFS.
In the present study we performed allelotype and haplotype analyses to establish linkage of IFS to 11q13 and to define the candidate interval of the IFS gene. As the age of diagnosis (<30 yr) and the cell specificity (somatotropes) of CNC-associated pituitary tumors are strikingly similar to those of IFS, we also performed linkage analysis and allelotyping using polymorphic microsatellite markers from chromosomes 2p and 17q (the CNC genetic loci), to determine whether the putative genes responsible for CNC might also play a role in the pathogenesis of IFS.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Detailed clinical and laboratory information for the 2 IFS families analyzed in this study (A and B) have been previously published (18). In family A, 3 (brothers) of 4 siblings are affected, with ages at diagnosis of 19, 21, and 23 yr. In family B, 5 (2 brothers and 3 sisters) of 13 siblings exhibit the phenotype and were diagnosed at 13, 15, 17, 17, and 24 yr of age. Two individuals from family A and all affected individuals from family B underwent surgical resections. The parents in both families were unaffected and had no history of consanguinity. In family B, the father’s brother died at the age of 18 yr from a "brain tumor" and was reported to have coarse features. Genetic study of both families was approved by the institutional review board of the University of Illinois at Chicago, and informed consent was obtained from all subjects.
Haplotyping and allelotyping
Peripheral blood samples were collected from all 8 affected
individuals, their parents, and unaffected siblings. Paraffin-embedded
pituitary adenoma tissue was obtained from the seven in whom pituitary
surgery had been performed. DNA was extracted from leukocytes and tumor
samples as previously described (18). Sixteen polymorphic
microsatellite markers from chromosome region 11q12.3–11q13.5 were
analyzed: D11S956, D11S1335, D11S1253, D11S4191, D11S4076,
D11S4205, D11S480, D11S1883, PYGM, D11S4941, D11S4908, D11S1889,
D11S4095, D11S987, INT-2, and D11S527 (in centromeric
to telomeric order). We used polymorphic microsatellite markers
D2S378 and D17S949 from chromosomes 2p16–15 and
17q23–24, respectively, for the initial screening. The following
polymorphic microsatellite markers were used for additional studies on
chromosome 2: D2S367, D2S177, D2S2306, D2S119, D2S288, D2S391,
D2S2378, D2S123, D2S2165, D2S337, D2S147, D2S2320, D2S2349, D2S2110,
D2S286, D2S139, D2S388, and D2S113 (in telomeric to
centromeric order). The location and order of markers are as described
in the Genethon human genetic linkage map
(http://www.genethon.fr/genethon_en/html) (23) and the GB4 and G3
radiation hybrid maps [http://www.sanger.ac.uk,
http://shqc.stanford.edu and recently identified markers on chromosome
11q13 (24)]. Primer sequences were obtained from the Genome Database
(http://www.gdb.org). One oligonucleotide of each primer pair was end
labeled with [
-32P]ATP using the 5' DNA
Terminus Labeling System kit (Life Technologies, Inc.,
Grand Island, NY) or with a 6-carboxyfluorescein or a
4,7,2’,7’,-tetrachloro 6-carboxyfluorescein fluorescent dye
(Perkin-Elmer Corp., Foster City, CA). PCR reactions were
performed in a total volume of 20 µL containing 100–200 ng leukocyte
DNA or 1–2 µL tumor DNA (equivalent to 1–2% of 15–20 5-µm
paraffin sections), 1 x PCR gold buffer (Perkin-Elmer Corp.), 1.0–1.5 mmol/L MgCl2, 0.2 mmol/L
deoxy (d)-NTPs (Roche Molecular Biochemicals,
Indianapolis, IN), 0.25 µmol/L primers, and 2.5 U AmpliTaq Gold
(Perkin-Elmer Corp.). A hot start was performed at 95 C
for 10 min, and each of the 40 subsequent cycles consisted of
denaturation at 95 C for 45 s, annealing at 55–62 C for 45
s, and extension at 72 C for 60 s, followed by a final extension
at 72 C for 15 min. The MgCl2 concentration and
annealing temperature varied with the specific primers used. Aliquots
of the radiolabeled PCR products were electrophoresed in a 6%
polyacrylamide-8.3 mol/L urea gel and visualized by PhosphorImager
(Molecular Dynamics, Inc., Sunnyvale, CA) or
autoradiography. Gel electrophoresis, data collection, and analysis of
the fluorescent-labeled PCR products were carried out on a 377 DNA
sequencer with GENESCAN software (Perkin-Elmer Corp.). In
the allelotype analyses, constitutional (leukocyte) and tumor DNA were
run adjacently, and LOH was defined as a greater than 50% decrease in
one of the expected PCR products in tumor DNA compared with leukocyte
DNA.
Linkage analysis
Two-point logarithm of the odds (LOD) scores were calculated using the MLINK program from the FASTLINK package (http://linkage. rockefeller.edu). The LOD score represents the statistical likelihood of linkage between two genetic loci. LOD scores of 3 or more (odds in favor of linkage, 1000:1) are generally accepted as evidence of linkage, and LOD scores of -2 or less (odds in favor of nonlinkage, 100:1) are taken as evidence that two loci are not linked. Isolated familial somatotropinoma was modeled as a rare autosomal dominant disease with incomplete penetrance. Therefore, penetrance of IFS was set at a level of P = 0.9 for both sexes, and the disease gene frequency was set at 0.0001. Equal allele frequencies were assumed because no reliable published data were available for the racial background of these families, and it was not possible to determine allele frequencies from the pedigrees due to the very limited size of available family members. The LOD scores were not significantly changed by alterations in allele frequencies.
Incorporation of information from LOH analyses into the two-point LOD score calculations has been previously described in detail (25, 26, 27). In conventional linkage analysis, the genotype at the disease locus is inferred from the penetrance, which is the probability of the phenotypic expression, given the genotype. When LOH is present, this additional information assists in inferring the disease genotype. If, according to Knudson’s two-hit hypothesis (28), the marker allele lost by LOH and the disease allele retained in the tumor are on the same haplotype, the genotype phase between the marker locus and disease locus is given, and an otherwise uninformative "phase unknown" meiosis may become informative for linkage. Inclusion of LOH information into the formulation of penetrance permits a simple modification of the conventional routines for MLINK or FASTLINK, which enhances their power to detect linkage.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Haplotypes from 6 members of family A and 13 from family B were
constructed using markers located at chromosome 11q12.3–11q13.3. In
family A, the parents were heterozygous for only markers
D11S4191, PYGM, and D11S4941. The 3 affected
sons, but not the unaffected daughter, shared the identical paternal
and maternal haplotypes (Fig. 1A
). No
meiotic recombination events were observed in family A. Six markers
exhibited distinct paternal and maternal alleles, and allelotyping of
the somatotropinomas revealed loss of the maternal allele of all
markers tested (Fig. 2), indicating that
the germline mutation was transmitted by the father. A maximum 2-point
LOD score of 1.2 was generated for all markers at = 0.0 (Table 1).
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). The haplotype
22413323 between and including marker alleles D11S956 and
D11S4095 (bold numbers) was transmitted from the
father to all affected children (black circles and
squares). This haplotype was not inherited by the unaffected
siblings, with the exception of subject 13B, who is 11 yr old and,
therefore, was considered to have an unknown disease status for the
linkage analyses. A meiotic recombination event was detected in
affected individual 11B between markers D11S4095 and
INT-2 (open rectangle), indicating that the
region telomeric to and including marker INT-2 is not
involved in the pathogenesis of IFS. Phenotypically normal individuals,
3B (31 yr) and 7B (23 yr), also exhibited recombinant haplotypes (Fig. 1B, open rectangles, and Fig. 3). However, because of the incomplete
penetrance of IFS, one of these individuals may be a silent carrier,
and therefore, we did not consider these recombination events in
determination of the IFS gene candidate interval. Allelotyping of the
somatotropinomas from patients 2B, 4B, 11B, and 12B revealed loss of
the maternal allele of all informative markers tested (Figs. 2 and 3).
In contrast, the tumor from patient 10B showed retention of both
alleles at D11S956 and D11S1335 (Figs. 2 and 4), indicating that the region
centromeric to and including marker D11S1335 is not involved
in the pathogenesis of IFS. Haplotyping and LOH analysis demonstrated
that the disease allele cosegregates with the paternal marker alleles.
Two-point LOD score calculations confirmed linkage between IFS and
chromosome 11q markers (Table 1). Maximum two-point LOD scores for
markers that did not show meiotic recombination, D11S1883, PYGM,
D11S4941, and D11S4908, were 3.7, 4.0, 3.8, and 2.5,
respectively ( = 0.0; Table 1). The lower LOD scores for
markers D11S1883, D11S4941, and D11S4908,
compared to PYGM, are due to either missing data
(D11S1883) or noninformative allele sizes
(D11S4941 and D11S4908).
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Linkage analysis excluded linkage between IFS and marker
D17S949 in both families (Table 2). In addition, no LOH was detected in
any of the somatotropinomas. These results indicate that the putative
CNC gene located at chromosome 17q23–24 is not involved in the
pathogenesis of somatotropinomas in these families.
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Genotyping and linkage analysis using marker D2S378 in
family A generated a LOD score of -4.4 ( = 0.0; Table 3). However, genotyping of individuals
from family B using the same marker showed that all affected
individuals inherited the same paternal marker allele, which was not
transmitted to the unaffected subjects (Fig. 5). A LOD score of 2.5 was generated at
this locus ( = 0.0; Table 3 and Fig. 6B). Because of these contrasting
results, additional markers were evaluated. LOD scores of -0.3 were
obtained for markers D2S367 and D2S391 in family
A, and thus, an absence of linkage could not be definitely established
in this family. However, in family B, analysis of nine additional
markers that flank D2S378 revealed that the paternal
haplotype 3331243 between and including marker alleles
D2S119 and D2S388 (a distance of 
40 cM) was
transmitted to all of the affected but none of the unaffected subjects
(Fig. 6B). This large region encompasses the entire 6.4-cM region that
contains the CNC locus (13). Meiotic recombination events were detected
in affected individual 12B and unaffected individuals 1B (35 yr) and
13B (11 yr; Fig. 6B, open rectangles). Two-point LOD scores
of 2.5 were generated for five additional markers from chromosome 2p
(Table 3). The positive LOD scores, although less than 3, are
suggestive of the possible involvement of the putative CNC gene located
at chromosome 2p15–16 in the pathogenesis of IFS. Allelotyping
demonstrated no LOH at any loci in both families (Fig. 5 and data not
shown). Allelotyping of the somatotropinomas from patient 2B revealed
microsatellite instability not only with marker D2S378 (Fig. 5), but also with multiple markers on both chromosomes 2 and 11. This
observation probably reflects the aggressive nature of the tumor.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present report is the first to establish linkage of IFS to
chromosome 11q13. We obtained two-point LOD scores of 3.0 or more,
which is accepted as evidence for linkage, for five markers
(D11S4191, D11S1883, PYGM, D11S4941, and
D11S4095) from this chromosome region. The PYGM
marker produced a maximum two-point LOD score of 4.0 at = 0.0,
which represents 10,000:1 odds in favor of its linkage to the IFS gene.
Furthermore, through meiotic recombination analysis and allelotyping in
family B, we determined that the disease allele is located in an 8.6-cM
region that is flanked by markers D11S1335 and
INT-2 (Fig. 7). In 1997,
Yamada et al. (20) reported a Japanese IFS kindred in which
two brothers and a maternal uncle were affected and in whom the
somatotropinomas exhibited LOH at 11q13. Haplotype analysis revealed a
meiotic recombination event between markers D11S987 and
D11S534 in one of the affected brothers. Subsequently,
Tanaka et al. (21) reported the absence of germline mutation
in the coding region or exon-intron boundaries of the MEN-1
gene in this family, and tumor deletion mapping in both
somatotropinomas showed LOH at markers D11S457, PYGM, and
D11S449, but not at D11S1883. Therefore,
combining the results from their genetic analyses and those in family B
of the present report permits a restriction of the IFS genetic
candidate interval to a 5.8-cM region flanked by markers
D11S1883 and INT-2 (Fig. 7). MEN-1 is
located in this interval and cannot be completely excluded as a
candidate gene because it is conceivable that there may exist mutations
in the promoter, untranslated, or intronic regions of MEN-1
that may cause changes in the level or stability of the
MEN-1 transcript. However, the clinical dissimilarities
between IFS and MEN-1 (age at diagnosis of the somatotropinomas and the
predominant pituitary tumor subtype) together with the data from the
genetic analyses performed in IFS families favor the argument that
inactivation of another tumor suppressor gene located at 11q13,
distinct from MEN-1, is responsible for IFS. Meiotic
recombination analysis and allelotyping in additional IFS families will
be required to further narrow the IFS candidate interval. Finally,
tumor deletion mapping in the subset of sporadic somatotropinomas that
exhibit LOH at 11q13 but no MEN-1 mutation may assist in
defining an even smaller IFS candidate interval, thereby expediting the
process of identifying the putative IFS tumor suppressor gene.
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= 0.0)
to D17S949, a marker in the center of the CNC 17q23–24
interval, and of LOH at this chromosome region indicates that the
putative CNC gene located at 17q23–24 is not involved in the
pathogenesis of IFS. However, linkage analysis using marker
D2S378, which is contained within the CNC 2p15–16 interval,
gave conflicting results. Although a two-point LOD score of -4.4 was
generated for family A, further analysis using additional markers did
not definitively establish the absence of linkage (LOD scores of
-0.3). In contrast, a LOD score of 2.5 was obtained from family B with
D2S378 and five additional markers, indicating there is a
316:1 likelihood that IFS is linked to 2p16–12 in this family. As
allelotyping revealed no LOH at any of the markers tested, the putative
gene within 2p16–12 is probably an oncogene rather than a tumor
suppressor gene. Similarly, Stratakis et al. (36) reported
an absence of LOH on 2p16 (D2S123) in nine CNC tumors,
including one somatotropinoma. The presence of an oncogene is further
supported by the finding that region 2p15–16 is amplified in various
CNC tumors, including two somatotropinomas (9). In summary, this report establishes linkage of the tumor suppressor gene involved in the pathogenesis of IFS to chromosome 11q13.1–13.3 and identifies a potential second locus at chromosome 2p16–12. Evidence for digenic inheritance has been reported in several other diseases (37, 38, 39). Although this raises the possibility of a similar mechanism in IFS, a more extensive linkage analysis and assessment of chromosomal abnormalities at chromosome 2p, such as amplification, will be required to determine whether the putative CNC gene at chromosome 2p is also involved in the pathogenesis of IFS.
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Acknowledgments |
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Footnotes |
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Received July 22, 1999.
Revised October 7, 1999.
Accepted October 22, 1999.
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References |
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