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Frequent Germ-Line Succinate Dehydrogenase Subunit D Gene Mutations in Patients with Apparently Sporadic Parasympathetic Paraganglioma

Department of Pathology, Josephine Nefkens Institute [H. D., W. N. M. D., M. A., R. R. d. K.] and Departments of Surgery [H. v. U., D. M.] and Otorhinolaryngology [B. K. H. P.], Erasmus Medical Center, 1738 Rotterdam, the Netherlands, and Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands [W. J. M.]

	ABSTRACT

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
Purpose: Recently, familial paraganglioma (PGL) was shown to be caused bymutations in the gene encoding succinate dehydrogenase subunit D (SDHD). However, the prevalence of SDHD mutations in apparently sporadic PGL is unknown. We studied the frequency and spectrum of germ-line and somatic SDHD mutations in patients with parasympathetic PGL.

Experimental Design: We studied 57 unselected patients who developed parasympathetic PGLs (n = 105 tumors) and who were treated between 1987 and 1999 at the Erasmus MC (Rotterdam, the Netherlands). Thirty-eight (67%) of these patients (n = 51 tumors) lacked a family history of parasympathetic PGL. We used conformation-dependent gel electrophoresis and sequence determination analysis of germ-line and tumor DNA to identify SDHD mutations. We compared the clinical and molecular characteristics of sporadic and hereditary PGLs.

Results: Three different SDHD germ-line mutations were identified in 32 of the 57 (56%) patients. These included 19 of 19 (100%) patients with familial PGL and also 13 of 38 (34%) patients with apparently sporadic PGL. All three mutations were characterized as missense mutations (D92Y, L95P, and L139P) in highly conserved regions of the SDHD gene and were not observed in 200 control alleles. No somatic mutations were found.

Conclusions: Germ-line mutations of the SDHD gene are present in a significant number of patients with apparently sporadic parasympathetic PGL. Somatic SDHD mutations do not play a significant role in the sporadic form of this tumor. Genetic testing for SDHD germ-line mutations should be considered for every patient presenting with this tumor, even if a personal or family history of PGL is absent, to allow appropriate clinical management.

	Introduction

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Parasympathetic PGLs³ are highly vascularized, slow-growing tumors of parasympathetic ganglia, mostly of the head and neck region. The annual incidence is estimated at 1 in 30,000, and the tumors typically present in the fourth or fifth decade (1 , 2) . The tumor most commonly presents as a painless neck mass or with symptoms due to compression and damage of the surrounding structures. Depending on the anatomical localization, cranial nerve damage may cause bradycardia, hoarseness, or hearing loss. Approximately 1% of the tumors produce catecholamines. Progression to malignancy occurs in 2–10% of cases and can only be determined by detection of metastatic spread, particularly to the lymph nodes and lungs. There are currently three treatment strategies: (a) surgery; (b) radiation therapy; or (c) observation (3) . Because tumor growth as well as surgery can cause disabling loss of function, preoperative estimation of tumor growth is an important parameter influencing clinical management. A "wait and scan" approach is thus often considered, although surgical resection remains the mainstay of the curative treatment of parasympathetic PGLs (4 , 5) .

Familial occurrence is observed in a significant minority (approximately 20%) of cases, with an autosomal dominant mode of transmission with incomplete and age-dependent penetrance (6, 7, 8) . The female predominance in sporadic PGL with equal sex distribution in familial patients and an almost exclusively paternal inheritance pattern in these families suggest maternal imprinting of the disease gene (9) . Clinical features that suggest a genetic predisposition in a given patient include bilateral or multiple PGLs and an unusually young age (before the third decade) at presentation. Linkage analysis and loss of heterozygosity studies in unrelated and multigenerational families with hereditary PGL (Mendelian Inheritance Man number 168,000) have provided evidence for the existence of two distinct PGL susceptibility genes on chromosome 11, PGL1 at 11q23 and PGL2 at 11q13, both of which are thought to be maternally imprinted (10 , 11) . Recently, the SDHD gene, which maps to the PGL1 locus, has been implicated as the putative disease gene because inactivating germ-line SDHD mutations have been detected in PGL families (12) . SDHD germ-line mutations were also recently described in a few cases of familial pheochromocytoma, and to date, only one sporadic mutation has been reported (13) .

The SDHD gene, which comprises four exons and three introns extending over 19 kb, encodes a 159-amino acid protein. This protein constitutes the small subunit (cybS) of cytochrome b in the mitochondrial enzyme complex II (succinate-ubiquinone oxidoreductase) and plays an important role in both the citric acid cycle and the aerobic respiratory chain (14) . Recently, it has been demonstrated that germ-line mutations in succinate dehydrogenase subunit C (SDHC) and succinate dehydrogenase subunit B (SDHB), encoding two other components of complex II, also predispose individuals to hereditary PGL (15 , 16) .

Whether genetic alterations of the SDHD gene play a role in the pathogenesis of sporadic parasympathetic PGL is presently unknown. Also, the prevalence of germ-line SDHD mutations among apparently sporadic PGL patients has not been studied. Further knowledge of the contribution and nature of gene mutations involved in PGL tumorigenesis could provide early diagnosis and allow accurate genetic counseling in affected families. Therefore, we assessed the frequency and type of SDHD mutations in an unselected series of patients with parasympathetic PGLs treated at our hospital, including both familial and apparently sporadic cases.

	Patients and Methods

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Patients.
Individuals who received a diagnosis of parasympathetic PGL between May 1987 and December 1999 were identified by retrospectively reviewing the records of the Pathology Department at the Erasmus MC. Of the 89 PGL patients eligible to participate, specimens and constitutional DNA from 57 patients were available for retrieval and testing. Information on medical and family histories was obtained by direct interviews and by review of the medical charts. The presence of multiple tumors was assessed by review of the radiology reports of SRS and/or magnetic resonance imaging. From 48 patients, SRS and/or magnetic resonance imaging reports were available [41 patients (72%) underwent SRS]. Of the nine patients without such information, four had histopathological diagnoses of bilateral or multiple tumors. The average follow-up period was 52 months (range, 1–218 months), with no significant difference between familial and apparently sporadic patients.

A total of 105 parasympathetic PGLs was observed in the 57 patients, of which 78 tumors and matched normal tissues were available for analysis. After coupling of the clinical information to the pathology specimen, both patient information and DNA samples were anonymized to preserve the confidentiality of the patients and in accordance with the Erasmus MC guidelines for studies involving patient data and tissues. A tumor was considered sporadic if the patient did not know any relative with PGL.

Control DNA consisted of 100 encoded peripheral blood samples from persons residing in the same geographic area, randomly selected from the blood bank (Bloedbank ZWN Rotterdam, the Netherlands).

In addition, 13 PGLs from 13 patients residing in other geographic areas (from hospitals in the south of the Netherlands and Belgium) were investigated for exon 3 SDHD mutations.

Clinical Database.
A collective database of clinical and molecular features was prepared. The date of the patient’s first biopsy or resection with a histopathological diagnosis of parasympathetic PGL was recorded as the date of diagnosis. The age of onset was defined as the age at which the patient first experienced symptoms. Three patients (two women and one man) were related to one another, and an additional two patients belonged to another family. For each patient, we recorded the place of birth, age of onset and diagnosis, clinical history, the patient’s family history with respect to parasympathetic PGL, the laterality/multifocality of the tumors, and the presence of any metastases.

DNA Preparation and SSCP Analysis.
Fresh frozen or formalin-fixed, paraffin-embedded tumor and normal tissues from all patients, including 78 of the 105 tumors, were retrieved from the archives of the Pathology Department of the Erasmus MC. Paraffin blocks containing tumor and normal tissues were obtained from 13 patients residing in other areas [kindly provided by Prof. Dr. E. Van Marck (Department of Pathology, University Hospital Antwerp, Antwerp, Belgium), Dr. G. van Lijnschoten (Society for Pathological Anatomy and Medical Microbiology, Eindhoven, the Netherlands), and Dr. A. P. de Bruïne (Department of Pathology, University of Maastricht, Maastricht, the Netherlands)].

From each specimen, regions containing at least 80% neoplastic cells were selected. DNA from 12 freshly frozen tumors was isolated using the D-5000 Pure gene DNA isolation kit (Gentra Systems, Minneapolis, MN) according to the manufacturer’s recommendations. DNA from 66 paraffin-embedded tumors and all normal tissues was extracted by standard detergent-proteinase K lysis, followed by phenol-chloroform extraction and ethanol precipitation, as described previously (17) .

The entire open reading frame of the SDHD gene and all exon-intron boundaries were investigated with the PCR primers described previously (12) . PCR amplification of tumor DNA and matched normal DNA was performed in 15-µl reaction mixtures containing 1.5 mM MgCl₂; 10 mM Tris-HCl; 50 mM KCl; 0.02 mM dATP; 0.2 mM dGTP, dTTP, and dCTP; 0.8 µCi of [-³²P]dATP (Amersham, Buckinghamshire, United Kingdom); 20 pmol of each sense and antisense primer; and 1 unit of Taq DNA polymerase (Amplitaq Gold; Perkin-Elmer, Norwalk, CT). The amplification profile consisted of an initial denaturation step at 94°C for 5 min, followed by 35 cycles of denaturation at 94°C for 45 s, annealing at 55 for 60 s, and extension at 72°C for 60 s. A final extension step was carried out at 72°C for 10 min. Electrophoresis of PCR products was carried out overnight at 8 W on nondenaturing gels containing 8% polyacrylamide (49:1) and 10% (v/v) glycerol. For the exon 4 amplicons, electrophoresis was performed on an 8% polyacrylamide gel without glycerol for 6 h at 4°C and 20 W. The gels were dried and exposed to X-ray film overnight at -70°C.

DNA Sequencing.
For each variant pattern identified by SSCP analysis, two independent genomic DNA samples were amplified for direct sequencing, or the aberrant PCR product was cloned and reamplified with the original primer pair. These products were bidirectionally sequenced using Applied Biosystems Taq DyeDeoxy terminator cycle sequencing (Baseclear, Leiden, the Netherlands).

Statistics.
Correlations between a specific SDHD mutation and clinical features were tested by use of the ² test or an unpaired t test. Ps < 0.05 were considered statistically significant.

	Results

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Patient Characteristics.
The characteristics of the patients and their tumors are shown in Table 1 . The group of 19 patients with a positive family history of PGL showed a roughly equal sex distribution (42% male versus 58% female), whereas there was a female predominance in patients without a family history of PGL (34% male versus 66% female). The mean age at onset was earlier in patients with a positive family history (P = 0.04). The majority of patients with a single PGL tumor had no family history, and bilateral carotid body tumors and multiple tumors were generally associated with a positive family history (P < 0.0001).

None of the patients had evidence of metastatic disease at the end of our study. Of the 57 patients, only 1 young patient (1.8%) had evidence of a malignant PGL (tumors cells were detected in one lymph node after total resection of a carotid body tumor). After 141 months of follow-up, she is alive and well.

Seven patients developed a recurrence after resection of a single PGL, which was either a tympanic, jugular, or vagal tumor. None of these patients had a positive family history.

Identification of SDHD Gene Mutations.
SSCP analysis revealed four different aberrant patterns, which were present in 49 of 78 (63%) PGL specimens. In each instance, the same SSCP variant was also found in the germ-line DNA of the patient (totaling 33 of 57 patients; 58%). By sequence analysis, the aberrant patterns, which were all located in exon 3 and exon 4, were found to correspond to three different missense SDHD mutations and one SNP. All three missense mutations were located in highly conserved regions and were absent from the 200 control alleles. The specific D92Y missense mutation was observed in 22 patients, the L95P mutation was observed in 9 patients, and the L139P mutation was observed in 1 patient. Altogether, germ-line SDHD missense mutations were identified in 32 of 57 (56%) patients.

The SNP, which does not result in an amino acid substitution in the SDHD protein, involved a change in codon 68 (AGCAGT). This sequence alteration was also observed in one of the 200 control alleles and is therefore regarded as an uncommon polymorphism apparently not associated with hereditary PGL.

Examples of SSCP analysis and sequence determination in patients with SDHD missense mutations are shown in Fig. 1A .

View larger version (43K): [in this window] [in a new window]   Fig. 1. SDHD alterations identified in PGL patients by SSCP analysis and direct sequencing. SSCP patterns of the tumor (T) and germ-line (N) DNA are shown from all SDHD alterations. C, normal control sample. A shows the three missense mutations (D92Y, L95P, and L139P, respectively). B shows two new mutations found in 5 of 13 patients residing in other geographic areas. Left, the frameshift mutation caused by deletion of the first thymidine in codon 93, resulting in a premature stop codon in exon 4. Right, the splice site mutation (agat) at the boundary of intron 2 and exon 3 is shown. The autoradiographs of PCR-SSCP gels show the migration patterns of normal DNA (black arrowheads) and the mobility shifts produced by aberrant alleles (red arrowheads). The sequencing chromatograms below each autoradiograph show the alterations (note the substituted nucleotide marked by an asterisk). In samples that were cloned before sequencing, the normal sequence is absent, whereas in direct sequenced samples, both normal and aberrant sequences are present.

SDHD Mutations in Patients Residing in Other Geographic Areas.
To further investigate whether the recurrent mutations could be regarded as founder mutations, we analyzed 13 patients from hospitals in the south of the Netherlands and Belgium for exon 3 mutations. Five (38%) of these patients harbored a germ-line SDHD mutation in exon 3, including the Dutch founder mutation D92Y (three patients), a mutation resulting in a change of a splice site (5' intron 2-... gtat-3' exon 3), and a frameshift mutation caused by deletion of the first thymidine in codon 93 and resulting in a premature stop codon in exon 4 (Fig. 1B) .

	Discussion

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
PGL is the only well-documented manifestation of the hereditary PGL syndrome, in which SDHD gene mutations apparently represent an early and essential pathogenic event (12) . We identified SDHD mutations in 32 of 57 (56%) unselected patients. This supports the prediction that the SDHD gene has an important role in the pathogenesis of parasympathetic PGL. All SDHD mutations identified in this study were present in the patients’ germ-line DNA, including >30% of patients with a negative family history for PGL. These data indicate that family history is a poor indicator of the risk of hereditary PGL and that screening for germ-line SDHD mutations is clinically relevant in all patients presenting with parasympathetic PGLs.

SSCP screening for the presence of mutations revealed four different aberrant patterns. Upon sequencing, three aberrations proved to be missense mutations (D92Y, L95P and L139P), whereas the remaining one was a silent substitution SNP. These mutations could theoretically be clinically unimportant polymorphisms. However, we regard the missense mutations found in this study as pathogenic because they occur at highly conserved residues of the SDHD protein, they were absent from 200 control alleles, and finally, the D92Y and L95P mutations have been reported independently as pathogenic in familial PGL (12 , 18) .

All SDHD mutations identified in our study were present in the germ-line DNA; no somatic SDHD mutations were found. Recently, one somatic SDHD mutation was described in a pheochromocytoma (13) . These results imply that the involvement of the SDHD gene is restricted to inherited cases of PGL.

It is of interest that only three different SDHD mutations were found in the 32 patients with mutated SDHD, with two of them, D92Y and L95P, comprising 97% of the mutations detected in this study. This indicates that either these mutations are ancient or that the affected persons are more closely related than known. Information on places of birth in this cohort of patients is suggestive of a founder effect, although some of the patients originate from other European and non-European countries. Baysal et al. (12) previously reported the specific D92Y mutation in a Dutch founder population (19) . To further investigate whether this founder mutation occurs in patients from other geographic areas, we analyzed 13 patients from hospitals in the south of the Netherlands and Belgium for exon 3 mutations. Aside from the Dutch founder mutation, we also found two new mutations, supporting evidence for founder effects.

The finding of the same germ-line SDHD mutations in familial and sporadic cases points most likely to reduced penetrance of the mutated SDHD gene, although the occurrence of de novo hot spot mutations cannot be completely ruled out. Mutational and haplotype analysis of patients and family members would provide additional information on the origin of the mutations.

In all of the 19 familial PGL patients, a SDHD mutation was detected, indicating a high mutation detection sensitivity for SSCP analysis. However, in the apparently sporadic PGL patients, we cannot rule out the possibility that SDHD mutations escaped detection by SSCP (20) . Furthermore, mutations can be present in the SDHD gene outside the screened sequences. It is known that gene mutations in the untranslated regions can severely affect RNA stability. Finally, in some apparently sporadic patients, a germ-line mutation in another gene may cause PGL. Recently, germ-line mutations in the SDHC and SDHB genes have been demonstrated to cause autosomal dominant PGL syndromes as well (15 , 16) .

As shown, a positive family history of PGL is the main parameter associated with SDHD gene mutations (19 of 19 patients), followed by the presence of bilateral or multiple PGLs (24 of 27 patients). Importantly, in patients without a family history of PGL, bilateral or multiple tumors, but not early age at onset, pointed toward a germ-line SDHD gene mutation. In the 28 patients presenting with a single PGL tumor and lacking a family history of PGL, six germ-line SDHD mutations were found (21%). No clinical parameter was significantly correlated with any of the three mutations, but the study size precludes the detection of small differences.

These results show that clinical and patient data have limited value in indicating germ-line SDHD mutations. Comparable results were reported for apparently sporadic medullary thyroid carcinoma patients, who appeared to have germ-line RET gene mutations in about 10% of cases (21) . The authors show that, despite this low percentage, the genetic analysis of all apparently sporadic medullary thyroid carcinoma patients is cost-effective.

Genetic counseling on the basis of DNA linkage analysis in PGL families has previously been described by Oosterwijk et al. (22) . Their results indicate that screening of all PGL patients may further affect counseling strategies because the detection of germ-line SDHD mutations in apparently sporadic patients is likely to improve early diagnosis of PGL, which will support adequate and appropriate clinical follow-up and management. On the other hand, we have no data on the lifetime risk of PGLs in people harboring a germ-line SDHD mutation. More data are needed to allow a valid estimate of the risk of parasympathetic PGL in patients with SDHD mutations. However, our data do support the conclusion that SDHD mutation screening should be considered in every patient presenting with this tumor.

	ACKNOWLEDGMENTS

 
We are grateful to several people from the Department of Pathology, Josephine Nefkens Institute, Erasmus MC: Monica Seijbel for excellent secretarial assistance and Frank van der Panne for assistance in generation of the figures. We are also indebted to Prof. Dr. E. Van Marck, Dr. G. van Lijnschoten, and Dr. A. P. de Bruïne, who kindly provided PGL specimens. We thank Prof. Dr. S. W. L. Lamberts and Dr. P. C. Ewing-Graham for critical reading of the manuscript.

	FOOTNOTES

 
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 H. D. and W. N. M. D. contributed equally to this work.

² To whom requests for reprints should be addressed, at Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, P. O. Box 1738, 3000 DR Rotterdam, the Netherlands. Phone: 31-10-4088389; Fax: 31-10-4089487; E-mail: dinjens{at}path.fgg.eur.nl

³ The abbreviations used are: PGL, paraganglioma; SDHD, succinate dehydrogenase subunit D; SRS, somatostatin receptor scintigraphy; MC, Medical Center; SSCP, single-strand conformational polymorphism; SNP, single-nucleotide polymorphism.

Received 4/16/02; accepted 4/17/02.

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