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Sporadic Pheochromocytomas Are Rarely Associated with Germline Mutations in the vhl Tumor Suppressor Gene or the ret Protooncogene¹

Laboratory of Oncology, Womens Hospital Eppendorf (H.B., T.W.), and Institute for Hormone and Fertility Research (W.H.), University of Hamburg, Hamburg; and the Laboratory of Molecular Pathology, Institute of Pathology and Pathological Anatomy, Technical University (H.J.), and the Endocrinology Unit, Department of Medicine II, Ludwig Maximilian University (D.E., M.M. R.), and the Department of Surgery, Hospital Maria-Martha (F.S.), Munich, Germany

Address all correspondence and requests for reprints: to Dr. Hiltrud Brauch, Laboratory of Oncology, Womens Hospital Eppendorf, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.

	Abstract

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Pheochromocytoma is a tumor that may occur sporadically or may be a manifestation of a hereditary disease, such as von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia (MEN) type 2. As patients with VHL or MEN type 2 are at risk to develop multiple tumors, they must be distinguished from sporadic cases. We determined the incidence of VHL and MEN type 2 among 62 German patients diagnosed with pheochromocytoma without a history of a hereditary disease. Germline analyses of the vhl gene and exons 10, 11, and 13 of the ret protooncogene were performed by PCR, single strand conformation polymorphism, enzyme digestion, or sequencing. Two patients (3%) showed vhl mutations (95% confidence interval, 1–11%). One patient showed loss of the MspI restriction site at nucleotides 712/713. Another patient had a C/T change at an intronic site that was also detected in 2 of his offspring. No mutations were detected in the ret protooncogene (97.5% confidence interval, 0–6%).

In Germany, most sporadic pheochromocytomas are not due to VHL or MEN type 2. Therefore, clinical work-up in patients with pheochromocytoma without signs of hereditary disease is not recommended. However, because the costs of genetic screening are relatively low, and each index case allows optimal care for family members, molecular testing might be cost-effective.

	Introduction

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PHEOCHROMOCYTOMAS develop from chromaffin cells of the adrenal gland as well as those of extraadrenal sites. These tumors rarely show a malignant course. However, due to their production of bioactive catecholamines, they frequently cause life-threatening cardiovascular complications. Because most pheochromocytomas develop sporadically, their surgical removal offers a definite cure, although long term follow-up is necessary to detect possible recurrence or metastases. Pheochromocytomas may also be a manifestation of hereditary syndromes, i.e. von Hippel-Lindau disease (VHL), multiple endocrine neoplasia (MEN) types 2A and 2B, and neurofibromatosis (NF) type 1. Whenever a patient is diagnosed with pheochromocytoma, it is crucial to establish whether the adrenal tumor is a manifestation of one of these hereditary diseases. In patients with an inherited predisposition to develop pheochromocytoma, there would be a considerable risk to develop bilateral pheochromocytomas as well as other somatic abnormalities. Failure to detect hereditary pheochromocytoma inevitably involves the lack of early curative management for this patient and all relatives that are carriers of this pathological trait.

Recently, the observation of a high frequency of hereditary pheochromocytomas in a group of patients with sporadic pheochromocytomas led to the recommendation that all pheochromocytoma patients should be screened for VHL disease and MEN type 2 (1). Such screening requires morphological studies for detection of retinal, cerebellar, and spinal hemangioblastomas as well as renal cell carcinomas and pancreatic tumors in the search for VHL as well as a calcitonin stimulation test and measurements of serum levels of calcium and intact PTH in search for MEN type 2. These procedures are expensive, cumbersome, and unpleasant to the patients. Repeated testing throughout life is recommended to detect occult manifestations of these inherited disorders.

The underlying genetic defects for VHL and MEN type 2 are now known, allowing DNA-based germline screening to identify gene carriers and to assist the diagnosis of individuals at risk for VHL and MEN type 2 (2, 3). As gene carrier status is established from a blood sample and is independent of any clinical manifestations, germline mutation analyses can be performed presymptomatically. Thus, it is possible to distinguish pheochromocytoma of hereditary origin from that of somatic origin.

Recently, germline ret mutations have been reported in patients with sporadic pheochromocytomas without a family history of endocrine neoplasia (4). No data on the frequency of germline mutations in the vhl gene among patients with sporadic pheochromocytomas are available; however, several lines of evidence support this possibility. In VHL, de novo vhl germline mutations are not uncommon (5). Recently, we identified a pheochromocytoma-associated vhl founder mutation. We tested whether this founder mutation or any other vhl mutation resulted in an increased incidence of pheochromocytoma-associated VHL disease among apparently sporadic pheochromocytomas (6). In a series of 62 unselected patients from Germany with apparently sporadic pheochromocytomas analyzed for germline mutations within the vhl gene and at targeted regions within the ret protooncogene, we showed that these patients have a low probability of being gene carriers for VHL or MEN type 2.

	Subjects and Methods

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Subjects

We analyzed the constitutional DNA of 62 patients who had undergone surgery from 1995–1996 for sporadic pheochromocytoma at the Ludwig Maximilian University (n = 40) and Hospital Martha-Maria (n = 19) in Munich and at the Benjamin Franklin University in Berlin (n = 3). The diagnosis of pheochromocytoma was always made preoperatively by typical clinical and biochemical findings for catecholamine excess and was confirmed postoperatively by histological evaluation. Based upon history, physical examination, and family history, none of these individuals had clinical evidence of MEN type 2, VHL, or NF type 1. Patients were from 17–82 yr of age at diagnosis. Seventeen patients were younger than 40 yr, 29 patients were between 40–60 yr, and 16 patients were older than 60 yr. All patients gave informed consent.

Patient 1590 underwent clinical examinations for detection of VHL disease (computed tomography without contrast enhancement, abdominal sonography, and ophthalmological examination in mydriasis).

In addition, four siblings of patient 1639 and three offspring of patient 1590 were examined for vhl germline mutations.

DNA was isolated from peripheral blood leukocytes by standard methods.

vhl mutation testing

The constitutional DNA of 62 patients was analyzed for known frequent vhl mutations by mutation-specific tests. The founder mutation at nucleotide (nt) 505 (C/T, Tyr⁹⁸His), frequently associated with pheochromocytomas in VHL disease of patients from the Black Forest region in Germany, was tested with a specific primer-modified restriction map modification assay (6). DNA from a VHL patient with a known nt 505 C/T mutation served as a positive control. The hot spot mutation at nt 712/713 inactivates an MspI restriction site. The patients and 4 siblings of patient 1639 were specifically tested for the presence or absence of this restriction site (7). DNA from a VHL patient with a known hot spot mutation served as a positive control. Documentation of restriction fragments was performed after electrophoresis with the INTAS DUO on-chip integration system from INTAS. In addition, vhl germline mutation analysis was performed in 53 patients by PCR and single strand conformation polymorphism (SSCP) in all 3 exons of the vhl gene. The PCR product of exon 2 of patient 1590 with an aberrant SSCP pattern and the PCR products of his 3 children were sequenced. PCR and sequencing primers as well as all methods were previously reported (8). Earlier, these methods allowed us to detect vhl germline mutations in 27 of 28 (96%) families with pheochromocytoma-associated VHL, which contributes to 81 of 101 (80%) detectable vhl mutations in families with VHL (6, 8) (our unpublished observations).

ret mutation testing

Targeted regions within exon 10 (codons 609, 611, 618, and 620) and exon 11 (codon 634) were analyzed by PCR, SSCP, and restriction enzyme digest (9, 10). Exon 13 was amplified by PCR and analyzed by DNA sequencing using the Prism ready reaction dideoxy terminator cycle sequencing kit from Perkin-Elmer and run on the automated sequencing system 377 from Applied Biosystems (Foster City, CA). Descriptions of the methods may be obtained from us upon request.

	Results

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Germline vhl mutations

The primer-modified restriction map modification assay failed to detect the founder mutation at nt 505 in all 62 patients. Enzymatic digestion of the amplified exon 3 showed a hot spot mutation in 1 (1639) of 62 patients. Combined PCR and SSCP analyses of the coding region and intron/exon boundaries of the vhl gene in 53 patients detected an abnormal SSCP pattern for the amplified exon 2 segment in 1 patient (no. 1590). Sequencing analysis of both complementary DNA strands identified an intronic point mutation at position 676+8. Figure 1a shows this C/T change and the corresponding G/A change of the reverse strand. Figure 1b shows the loss of an MspI restriction site in patient 1639 involving the mutation hot spot at nt 712/713. The total of 2 identified vhl mutations in 62 patients refers to a 95% confidence interval of 1–11%.

View larger version (64K): [in this window] [in a new window]   Figure 1. a, Germline sequencing analysis of the exon 2 segment of the vhl gene of patient 1590 with a sporadic pheochromocytoma. The sequence in the 5'-3' direction shows a C/T change (arrowed) at nt 676+8, which is confirmed as a G/A change (arrowed) when sequenced in the 3'-5' direction. b, Example of an MspI digest and agarose gel electrophoresis of the exon 3 segment in 13 patients with sporadic pheochromocytoma. M, Mol wt marker Boehringer Mannheim V; P, positive control. The fragment at 280 bp (I) indicates loss of the MspI restriction site. N, Negative control, indicating the resulting normal fragments of 200 bp (II) and 80 bp (III). Number 7 refers to patient 1639, who also showed loss of this restriction site. All others showed normal restriction patterns.

Upon clinical screening, patient 1590 was free of eye, central nervous system, kidney, and bilateral adrenal lesions.

Germline ret mutations

PCR and SSCP analysis as well as DNA sequencing failed to identify ret mutations in all 62 patients in exons 10, 11, and 13, yielding a 97.5% confidence interval of 0–6%.

	Discussion

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We studied 62 unselected patients with sporadic pheochromocytoma for a genetic predisposition to VHL and MEN type 2. Establishing either of these diagnoses is important to the patient and the family because the risk of developing multiple pheochromocytomas and other tumors involves not only the proband but the entire family. Early detection of the lesions involved in both syndromes is important for successful management. Hemangioblastomas of the central nervous system and metastatic renal cell carcinomas in VHL, medullary thyroid cancer in MEN type 2, and pheochromocytomas in both syndromes are life-threatening conditions. For these reasons it is important to distinguish hereditary pheochromocytomas from those of sporadic origin.

Pheochromocytomas associated with VHL develop as a consequence of missense mutations in the vhl tumor suppressor gene in chromosomal region 3p25 (7, 8, 11). A frequent vhl missense mutation is a tyrosine to histidine change at codon 98, which was identified in pheochromocytoma-associated VHL of families from the Black Forest region in Germany (6). Another frequent vhl missense mutation involves an arginine to tryptophan or glutamine change at codon 167, which was identified in unrelated VHL families with pheochromocytomas (7, 11). Current knowledge about a biological function of the VHL protein indicates that it negatively regulates the transcription elongation factor, elongin (12). Pheochromocytomas associated with MEN type 2 correlate with specific missense mutations of the ret protooncogene in chromosomal region 10q11.2. Frequently affected are codons 609, 611, 618, 620, and 634 of highly conserved cysteine residues. In a small number of cases, mutations in exon 13 have been found (3, 4, 10). The ret protooncogene encodes a putative transmembrane tyrosine kinase regulated by glial cell-derived neurotropic factor, which is a member of the transforming growth factor-ß superfamily (13).

Recent developments in the identification and molecular analyses of the vhl and ret genes as well as in genotype-phenotype correlations have provided molecular tools to distinguish VHL from MEN type 2 and raised prospects for insight into the role of these cancer genes in the development of pheochromocytomas. The power of these techniques has proven adequate to establish and even revise clinical diagnosis in families with minimal disease phenotype (14, 15).

Differential diagnosis of sporadic vs. hereditary pheochromocytoma is hampered by minimal disease phenotypes and incomplete penetrance at the onset of the hereditary tumors (14, 15). Also, the discovery of geographic variations in the distribution of vhl germline mutations, i.e. a founder mutation in the Black Forest region in Germany (6) or a frequent vhl hot spot mutation (7, 11), raised the suspicion of an as yet unnoticed increased incidence of these germline mutations among pheochromocytoma patients. As the founder mutation developed at least 200 yr ago, by now it may have spread throughout the population. Analysis of the constitutional DNA of patients with sporadic pheochromocytomas did not reveal evidence of unidentified spread of the vhl founder mutation. In contrast, de novo vhl mutations are common (5). The lack of a family history in pheochromocytoma patients with de novo vhl mutations may mask their hereditary origin. As the most frequent mutation site in the vhl gene affects the hot spot at nt 712/713 (7, 11), the finding of such a hot spot mutation in a 33-yr-old male patient with pheochromocytoma may be assumed by the early age of onset. Lack of additional VHL manifestations and negative testing for this germline mutation in his four siblings support the idea of a de novo mutation with an as yet incomplete VHL phenotype. However, the finding of this hot spot mutation was not in keeping with the vast majority of pheochromocytoma patients younger than age 40 yr.

Another vhl germline variation with unknown biological consequence was identified in a 63-yr-old male without any signs of a hereditary tumor syndrome. It was located within the splice consensus sequence of intron 2. It matches neither any of the 32 identified vhl germline mutations associated with pheochromocytoma in VHL nor any of the 300 germline vhl mutations identified worldwide (11). However, this DNA variant segregated to 2 of his 3 offspring. It is possible that this DNA sequence change is a very rare polymorphism despite the fact that it was not identified among more than 250 unrelated individuals (our unpublished observations). Upon clinical screening for eye, central nervous system, and abdominal lesions, no additional tumors were identified. Thus, the meaning of this DNA variation and its role in the development of pheochromocytoma remain unknown.

Neumann et al. described an increased incidence of VHL (19%; 16 of 82 patients) and MEN type 2 (4%; 3 of 82 patients) in patients with pheochromocytoma without a family history of the disease (1). This study was performed in patients from the Freiburg area in Germany. This area is part of the Black Forest region, which contains at least 15 families with the identical mutation in the vhl gene. In view of the fact that most vhl mutations identified in patients with sporadic pheochromocytoma from the Freiburg area were mutations involving nt 505, it appears that these results are not representative of other areas in Germany. In light of the findings that a large fraction of the then clinically identified pheochromocytomas are due to this vhl founder mutation (6), it must be concluded that there was a bias by a natural selection for VHL-associated pheochromocytoma. This is corroborated by the recent findings of the absence of germline mutations in the vhl gene and the ret protooncogene in 24 patients from Israel. These patients presented with solitary pheochromocytoma and were of different ethnic backgrounds (Bar et al.) (19).

A low incidence of vhl and ret germline mutations among patients with sporadic pheochromocytoma was recently reported by Eng et al. (16). ret mutations were identified in 10–20% of pheochromocytoma patients (16, 17, 18), but only one mutation was confirmed to originate in the germ line (16). Likewise, vhl mutations were identified in 8% of pheochromocytoma patients, but only one was a germline mutation (16). Both patients fulfilled at risk criteria for a hereditary disease, i.e. a family history of MEN type 2 or bilateral pheochromocytoma. Thus, these results differ from ours because both patients with vhl germline mutations in this study lack clinical evidence for a familial disease.

The risk for sporadic pheochromocytoma associated with VHL disease is 3% (95% confidence interval, 1–11%). No MEN mutation was found (97.5% confidence interval, 0–6%). This low incidence is remarkable because a large fraction of the patients analyzed in this study met the criterion of young age at onset as a risk factor for tumor development in individuals with a genetic predisposition. Our results show that the rare incidence of germline mutations in the vhl and ret genes in patients with sporadic pheochromocytoma put this group at low risk to develop additional somatic abnormalities. Consequently, recommendations for work-up of patients with pheochromocytoma should be restrained. It may not be justified to perform extensive clinical work-up without signs of hereditary disease. However, for the identification of rare hereditary pheochromocytomas, genetic screening might prove to be cost-effective, as each index case allows optimal care for family members, and the costs of molecular testing are relatively low.

	Acknowledgments

 
We are grateful to Prof. W. Oelkers (Benjamin Franklin University, Berlin, Germany) and Prof. D. Nast-Kolb (Surgery Department, Klinikum Innenstadt, Ludwig Maximilian University, Munich, Germany) for the data of eight patients, and to Dr. B. Zbar (NCI-FCRDC, Frederick, MD) for helpful comments on the manuscript.

	Footnotes

 
¹ This work was supported by grants from the Wilhelm Sander-Stiftung (no. 93.004.3) and Deutsche Krebshilfe (no. 70545).

Received February 19, 1997.

Revised July 23, 1997.

Accepted August 11, 1997.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brauch, H. Articles by Ritter, M. M. Search for Related Content PubMed PubMed Citation Articles by Brauch, H. Articles by Ritter, M. M.