Download Somatic and Occult Germ-line Mutations in SDHD

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Advances in Brief
Somatic and Occult Germ-line Mutations in SDHD, a Mitochondrial Complex II
Gene, in Nonfamilial Pheochromocytoma1
Oliver Gimm, Mary Armanios, Heather Dziema, Hartmut P. H. Neumann, and Charis Eng2
Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio
State University, Columbus, Ohio 43210 [O. G., M. A., H. D., C. E.]; Medizinische Universitätsklinik, Albert-Ludwigs-Universität, D79106 Freiburg, Germany [H. P. H. N.]; and
Cancer Research Campaign, Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, United Kingdom [C. E.]
Most pheochromocytomas are sporadic but about 10% are thought
to be hereditary. Although the etiology of most inherited pheochromocytoma is well known, little is known about the etiology of the more common
sporadic tumor. Recently, germ-line mutations of SDHD, a mitochondrial
complex II gene, were found in patients with hereditary paraganglioma.
We sought to determine whether SDHD plays a role in the development of
sporadic pheochromocytomas and performed a mutation and deletion
analysis of SDHD. Among 18 samples, we identified 4 heterozygous sequence variants (3 germ-line, 1 somatic). One germ-line SDHD mutation
IVS1ⴙ2T>G (absent among 78 control alleles) is predicted to cause
aberrant splicing. On reinvestigation, this patient was found to have a
tumor of the carotid body, which was likely a paraganglioma. Another
patient with malignant, extra-adrenal pheochromocytoma was found to
have germ-line c.34G>A (G12S). However, this sequence variant was also
found in 1 of 78 control alleles. The third, germ-line nonsense mutation
R38X was found in a patient with extra-adrenal pheochromocytoma. The
only somatic heterozygous mutation, c.242C>T (P81L), has been found in
the germ line of two families with hereditary paraganglioma and is
conserved among four eukaryotic multicellular organisms. Hence, this
mutation is most likely of functional significance too. Overall, loss of
heterozygosity in at least one of the two markers flanking SDHD was
found in 13 tumors (72%). All of the tumors that already harbored
intragenic SDHD mutations, whether germ-line or somatic, also had loss
of heterozygosity. Our results indicate that SDHD plays a role in the
pathogenesis of pheochromocytoma. Given the minimum estimated germline SDHD mutation frequency of 11% (maximum estimate up to 17%) in
this set of apparently sporadic pheochromocytoma cases and if these data
can be replicated in other populations, our observations might suggest
that all such patients be considered for SDHD mutation analysis.
most familial forms of pheochromocytoma is well known. Germ-line
mutations in the RET proto-oncogene are found in ⬎98% of MEN 2
patients with pheochromocytoma (5, 7), and germ-line mutations in
the tumor suppressor gene VHL are found in ⬎98% of VHL patients
with pheochromocytoma (8, 9). In contrast, little is known about the
etiology of the more common sporadic form of pheochromocytoma.
Somatic RET mutations have been found in up to 10% of tumors and
somatic VHL mutations in no more than 2% (10 –13).
Pheochromocytomas are also referred to as adrenal paragangliomas. Paragangliomas originate from the neural crest-derived paraganglia of the autonomic nervous system. They are identified throughout
the body in both adrenal and extra-adrenal sites. Hereditary paragangliomas are highly vascularized tumors located in the head and neck.
They are most commonly found at the bifurcation of the carotid artery
in the neck, also referred to as the carotid body. Recently, germ-line
mutations of SDHD were found in patients with hereditary paraganglioma (14). SDHD, located on 11q23 (15), encodes the small subunit
(cybS) of cytochrome b in the succinate-ubiquinone oxidoreductase
complex (mitochondrial complex II). This enzyme complex plays an
important role in both the tricarboxylic acid cycle and the aerobic
respiratory chain of eukaryotic cell mitochondria. SDHD comprises
four exons and three introns spanning over 19 kb (16).
We sought to determine whether SDHD plays a role in the development of sporadic cases of what has been defined as pheochromocytomas in the German-Polish Registry by analyzing the SDHD gene
for sequence variants and microsatellite markers flanking the gene for
LOH. Our results indicate that SDHD plays a role in the pathogenesis
of pheochromocytoma.
Introduction
Materials and Methods
Abstract
Pheochromocytomas produce and secrete catecholamines and,
hence, can cause hypertension. They derive from large pleomorphic
chromaffin cells that most commonly arise from the adrenal medulla.
In rare instances, pheochromocytomas are extra-adrenal. Most pheochromocytomas are sporadic but ⬃10% are hereditary (1, 2) and may
be found in association with the MEN 23 syndromes or VHL (3–5).
Isolated familial forms of pheochromocytoma without other associated clinical features occur even less commonly (6). The etiology of
Received 6/9/00; accepted 10/31/00.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
1
Partially supported by the National Cancer Institute, Bethesda, Maryland
(P30CA16058 to Ohio State University Comprehensive Cancer Center) and by generous
gifts from the Brown family in memory of Welton Brown and the Abrams family
(to C. E.).
2
To whom requests for reprints should be addressed, at Human Cancer Genetics
Program, The Ohio State University, 420 W. 12th Avenue, Room 690C TMRF, Columbus,
OH 43210. Phone: (614) 292-2347; Fax: (614) 688-3582 or (614) 688-4245; E-mail:
[email protected].
3
The abbreviations used are: MEN 2, multiple endocrine neoplasia type 2; VHL, von
Hippel-Lindau syndrome; LOH, loss of heterozygosity.
Patients and DNA Samples. Genomic DNA from tumor and peripheral
blood leukocytes was obtained from 18 unrelated patients (14 female, 4 male)
who underwent surgery for sporadic pheochromocytoma at the University of
Freiburg, Germany. All of the samples were obtained with informed consent.
The patients were selected from a population-based register that currently
holds 170 sporadic pheochromocytomas4. These 18 patients were chosen
because they were the only ones who had paired germ-line DNA and frozen
pheochromocytoma in the sample bank. All of the 18 pheochromocytomas
were classified as being sporadic because of the absence of germ-line mutations specific for MEN 2 (RET, localized to 10q11.2) and VHL syndrome
(VHL, 3p25–26; Ref. 5, 8). Furthermore, the patients’ personal and family
histories, as well as meticulous physical examinations, biochemical tests, and
imaging studies, were not suggestive of MEN 2, VHL, or NF 1 (3, 13, 17). Of
the 18 tumors, 4 pheochromocytomas were extra-adrenal, 3 of which were
malignant. Another intra-adrenal pheochromocytoma also was classified as
malignant. Malignancy was operationally defined as local infiltration of adja4
H. P. H. Neumann, S. Gläsker, B. U. Bender, T. W. Apel, R. Munk, O. Gimm, H.
Dziema, C. Smigielski, K. Zerres, A. Januszewicz, and C. Eng. High frequency of
inherited mutations causing pheochromocytoma in a registry-based cohort, submitted for
publication.
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SDHD MUTATIONS IN SPORADIC PHEOCHROMOCYTOMAS
Table 1 Summary of clinical features
Clinical feature
Cases with
germ-line
SDHD variant
Cases without
germ-line
SDHD variants
No. of casesa
Age at presentation (yrs)
Multifocal presentation
Intra-adrenal disease at presentation
Extra-adrenal disease at presentation
3
17–65
1
2
2
14
17–75
1
13
2
a
Single case with somatic mutation in tumor removed from clinical summary.
cent tissues and/or metastatic disease. Relevant clinical information is summarized in Table 1.
Genomic DNA from peripheral blood leukocytes from a region-matched,
race-matched control group was available. This group consisted of 39 individuals who were admitted to the Department of General Surgery, Halle, Germany, for nonpheochromocytoma-related diseases. Informed consent was
given in all of the cases.
DNA extraction was performed using the QIAamp tissue kit (Qiagen, Santa
Clarita, CA) according to the manufacturer’s instruction.
Mutation Analysis. PCR amplification was carried out in 1 ⫻ PCR buffer
(Qiagen) that contained 200 ␮mol/liter deoxynucleotide triphosphate, 0.6
␮mol/liter of each primer (14), 2.5 units of Taq polymerase (Qiagen), and
100 –200 ng of tumor DNA template in a 50 ␮l volume. PCR conditions were:
one cycle of 15 min at 95°C; 35 cycles of 1 min at 95°C; 1 min at 58°C; 1 min
at 72°C; followed by one cycle of 10 min at 72°C.
PCR amplicons were gel (Bio-Rad Laboratories, Hercules, CA) and column
(Wizard PCR Prep; Promega, Madison, WI) purified and subjected to semiautomated sequencing using the above primers, dye terminator technology, and
the ABI377xl or PE3700. If sequencing revealed a variant, the corresponding
leukocyte DNA was examined in the same manner to determine whether the
sequence variant was somatic or germ-line. Each sample with a sequence
variant was subjected to repeat mutation analysis that used a separate PCR
reaction.
LOH Analysis. All of the PCR reactions were carried out using 0.6 ␮M
each of forward and reverse primer in 1 ⫻ PCR buffer (Qiagen), 4.5 mM
MgCl2 (Qiagen), 1 ⫻ Q-buffer (Qiagen), 2.5 units of HotStarTaq polymerase
(Qiagen), and 200 ␮M deoxynucleotide triphosphate (Life Technologies, Inc.,
Gaithersburg, MD) in a final volume of 50 ␮l. Reactions were subjected to 35
cycles of 94°C for 1 min, 55– 60°C for 1 min, and 72°C for 1 min followed by
10 min at 72°C. LOH analysis was performed as described previously (18)
using the two markers flanking SDHD, D11S1347 (telomeric) and D11S1986
(centromeric). Both forward primers were 5⬘-labeled with either HEX or
6-FAM fluorescent dye (Research Genetics, Huntsville, AL). PCR reactions
were carried out as described above and separated by electrophoresis through
6% denaturing polyacrylamide gels using an Applied Biosystems model 377
automated DNA sequencer (Applied Biosystems and Perkin-Elmer Corp.,
Ridgeway, CA). The results were analyzed by automated fluorescence detection using the GeneScan collection and analysis software (GeneScan; Applied
Biosystems, Norwalk, CT). Scoring of LOH was performed by inspection of
the GeneScan analysis output. A double peak, observed in the microsatellite
marker that was amplified from DNA extracted from the germ-line sample,
indicated heterozygosity. A single peak in DNA extracted and amplified from
the corresponding tumor sample indicated a loss of one allele. If normal cells
were admixed with tumor cells, a ratio of 1.5:1 or greater of the germ-line
DNA peak:tumor DNA peak was operationally defined as LOH.
paraganglioma, and was scheduled for surgery. The IVS1⫹2T⬎G
variant was not found among 78 control alleles. Another patient, a
17-year-old female, was found to have germ-line missense mutation
G12S (c.34G⬎A, exon 1; Fig. 1A). Clinically, she had an extraadrenal, intra-abdominal pheochromocytoma. After surgery, catecholamine levels were normal but increased again. At 21 years of age,
she underwent reoperation because of recurrent extra-adrenal, intraabdominal pheochromocytoma. Because there was nodal involvement
within the jugular fossa, this pheochromocytoma was classified as
malignant. We then analyzed 78 control alleles and found this sequence variant in 1 allele from one patient with intestinal lipoma. This
patient’s general practitioner was contacted, and the clinical absence
of pheochromocytoma and paraganglioma was confirmed. A third
patient, a 33-year-old female, was found to have germ-line nonsense
mutation R38X (c.112C⬎T, exon 2; Fig. 1C). Clinically, she had two
extra-adrenal pheochromocytomas, one intra-abdominal tumor, and
one thoracic tumor.
The only somatic mutation c.242C⬎T, P81L (exon 3; Fig. 1D) was
Results
SDHD Mutation Analysis in Pheochromocytomas. Among 18
samples, we identified four heterozygous sequence variants in four
distinct samples (Fig. 1). Three of these were germ-line, and the
remaining one was somatic. A germ-line SDHD mutation
IVS1⫹2T⬎G (Fig. 1B) was detected in a 39-year-old male. Although
RNA was not available, this variant is predicted to cause aberrant
splicing. We then contacted this patient’s general practitioner, who
reported that this patient, at 43 years of age, had recently been
diagnosed with a tumor of the carotid body, which was likely a
Fig. 1. Somatic and germ-line SDHD sequence variants (denoted with arrowheads).
The affected codon and the amino acids are depicted below the chromatograms. Note that
the mutant chromatograms appear apparently heterozygous despite demonstration of LOH
of the wild-type allele likely because of admixed normal tissue contamination.
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SDHD MUTATIONS IN SPORADIC PHEOCHROMOCYTOMAS
Fig. 2. LOH analysis in pheochromocytomas; A, illustrative examples of LOH (arrows)
at D11S1986 (left panel), retention of heterozygosity (ROH) and noninformativity (NI) at
D11S1347 (right panel). GL, germline; Tu, tumor; B, summary of LOH data for the 18
tumor-germ-line pairs. f, LOH; 䡺, retention of heterozygosity; and o, noninformativity.
found to occur in a heterozygous state in a pheochromocytoma from
a 42-year-old female. This missense mutation was not found in
corresponding germ-line DNA.
LOH Analysis. Overall, LOH (Fig. 2) in at least one of the two
11q23 markers was found in 13 tumors (72%). LOH of both markers
was found in 3 tumors (17%). The remaining 10 tumors showed LOH
of one or the other 11q23 marker. All of the tumors already harboring
intragenic SDHD mutations also showed LOH.
Discussion
In our series of 18 apparently sporadic pheochromocytoma samples, we identified one (6%) somatic SDHD mutation and three (17%)
germ-line SDHD variants. The only somatic mutation, P81L, is almost
certainly pathogenic. It has also been found in the germ-line of two
families with hereditary paraganglioma (14). This missense mutation
is highly conserved in four eukaryotic multicellular organisms, and
the proline-leucine substitution in that position would be predicted to
alter cybS conformation (14). This tumor with somatic P81L also has
LOH of the remaining wild-type allele, which lends additional support
that the missense mutation is pathogenic and that SDHD is a tumor
suppressor gene that plays some role in the pathogenesis of sporadic
pheochromocytoma.
The nonsense germ-line R38X mutation is almost certainly pathogenic because it would likely result in a very short nonfunctional
protein. This mutation was also found by Baysal et al. (14) in the germ
line of one family with hereditary paraganglioma. The germ-line
IVS1⫹2T⬎G mutation occurs at one of the highly conserved consensus splice sequences and is almost certainly functionally significant inasmuch as it would be predicted to result in aberrant splicing.
Unfortunately, despite great efforts, no RNA is available. This germline variant has not been found in 78 regional control alleles, and
Baysal et al. (14) did not note the presence of this variant in 200 of
their control chromosomes either. That this patient developed a carotid body tumor, almost certainly a paraganglioma, 4 years subsequent to his diagnosis of isolated pheochromocytoma and that the
tumor had LOH of the remaining allele lend strong support that this
germ-line variant is actually an occult germ-line SDHD mutation that
predisposed to both the pheochromocytoma and the carotid body
tumor. Finally, the G12S germ-line variant that occurred in a teenager
with adrenal and extra-adrenal pheochromocytoma is somewhat of a
dilemma because it has been found in one regional control who did
not have any evidence of neuroendocrine tumors at the age of 72.
Baysal et al. (14), on the other hand, did not note G12S in their 200
normal control chromosomes. Nonetheless, we can postulate either
that this is a pathogenic but low-penetrance germ-line missense mutation that predisposes to pheochromocytoma or that this variant could
be a very rare polymorphism. Codon 12 is conserved between Homo
sapiens and the domestic cattle (14). In that position, an alteration
from a very small to a larger neutral and polar amino acid might have
some consequence; although without direct functional assay, it is open
to speculation. Given that the corresponding tumor had LOH of the
wild-type allele also lends some support that G12S may be somehow
pathogenic. Nonetheless, the conservative estimate of occult germline SDHD mutations that are likely pathogenic would be 11% if we
discount the G12S variant (see below).
The LOH frequency at the SDHD locus on 11q23 is worthy of note,
as well. LOH in pheochromocytomas has been reported on 1p (42–
71%), 3p25 (16 –56%), 17p (24%), and 22q (31–53%; Refs. 19 –22).
However, LOH on chromosome 11 in pheochromocytomas has not
been reported to date. We found LOH in at least one of the two
investigated markers on 11q23 in 72% of pheochromocytomas, a
significant frequency. Compared with this high frequency of LOH, the
frequency of functional mutations in SDHD (17%) is relatively low.
The 6% somatic mutation frequency in SDHD, however, is comparable with that of RET and VHL mutations. We suspect that in the
tumors with apparent hemizygous deletion, other epigenetic mechanisms, e.g., methylation of CpG islands in this region, may also play
a role in silencing SDHD similar to the inactivation of 14 –3-3␴ in
breast cancer (23). Because the promoter of SDHD has not been
identified yet (16), no further attempt to address this question has been
undertaken. Another explanation of our LOH data is that the LOH
actually reflects deletion of genes that neighbor SDHD and not SDHD
itself.
The molecular basis for sporadic pheochromocytomas has been
somewhat elusive. Allelotyping studies have revealed regions of LOH
(above). Despite relatively high frequencies of LOH in the VHL gene
region (3p25), ⬍2% of sporadic pheochromocytomas carry somatic
VHL mutations. Similarly, somatic RET mutations have been shown
to occur in 0 –10% of sporadic pheochromocytomas (10, 12, 24).
Although our data need to be confirmed in a larger series, they
strongly argue for a role of SDHD in the pathogenesis of sporadic
pheochromocytoma. It was of particular interest that we found not
only a somatic mutation but also occult germ-line variants, suggesting
a familial predisposition. Among prior series of apparently sporadic
pheochromocytoma presentations, occult germ-line mutations in VHL
and RET were found only in ⬃5% and ⬍2%, respectively (10, 13).
Thus, the minimum estimate of occult germ-line SDHD mutation
frequency of 11% (17% if the variant of unknown significance is
considered) found in these patients is significant. This mutation frequency is clinically important in the context that a preliminary survey
of the entire Registry, which comprises ⬃100 nonfamilial pheochromocytoma cases, also reveals an occult germ-line SDHD mutation
frequency of 10%.5 From this current study alone, it is not known
whether germ-line SDHD mutations in isolated pheochromocytoma
cases would predict for the development of extra-adrenal disease or
whether they could also predispose to a familial pheochromocytoma
only syndrome. Of interest, among the Registry cases as a whole, 70%
of those with germ-line SDHD mutations had intra-adrenal pheochromocytomas only, and 30% had extra-adrenal disease.5 Families with
5
H. P. H. Neumann, S. Gläsker, B. U. Bender, T. W. Apel, R. Munk, O. Gimm, H.
Dziema, A. Januszewicz, and C. Eng. Occult germline SDHD mutations in a registrybased pheochromocytoma cohort, manuscript in preparation.
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SDHD MUTATIONS IN SPORADIC PHEOCHROMOCYTOMAS
pheochromocytomas only (6) who do not have germ-line mutations in
RET and VHL should be scanned for mutations in SDHD on a research
basis in the first instance. Additionally, if further study proves that
occult germ-line SDHD mutations occur with the frequency reported
here or higher among apparently sporadic pheochromocytoma cases,
then routine SDHD mutation analysis might be considered in all such
presentations as well. Whether the presence of germ-line SDHD
mutations can predict for extra-adrenal disease or for the future
occurrence of extra-adrenal tumors in cases that present intra-adrenal
pheochromocytomas should be the subject of further study.
Acknowledgments
The authors are grateful to Dr. Margaret Ginn-Pease and Terry Bradley for
helpful advice and assistance with graphics and thank Drs. Cuong Hoang-Vu
and Henning Dralle for providing the control DNA.
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2000 American Association for Cancer
Research.
Somatic and Occult Germ-line Mutations in SDHD, a
Mitochondrial Complex II Gene, in Nonfamilial
Pheochromocytoma
Oliver Gimm, Mary Armanios, Heather Dziema, et al.
Cancer Res 2000;60:6822-6825.
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