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High Frequency of SDHB Germline Mutations in Patients with Malignant Catecholamine-Producing Paragangliomas: Implications for Genetic Testing

Section on Medical Neuroendocrinology, Reproductive Biology, and Medicine Branch (F.M.B., J.J.T., K.T.A., K.P.), National Institute of Child Health and Human Development; Clinical Neurocardiology Section (G.E.), National Institute of Neurological Disorders and Stroke; and Urologic Oncology Branch (W.M.L.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1109; and Division of Molecular Diagnostics (J.A.K.), Departments of Pathology and Human Genetics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc.., Building 10, CRC, Room 1E-1-3140, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109. E-mail: karel{at}mail.nih.gov.

	Abstract

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Context: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy.

Objective: We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma.

Design: SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations.

Results: Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%.

Conclusion: This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.

	Introduction

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CATECHOLAMINE-PRODUCING paragangliomas derive from chromaffin cells, mainly within the adrenal glands, and less commonly at extraadrenal sites (1, 2). Intraadrenal paragangliomas are commonly referred to as pheochromocytomas but are histopathologically indistinguishable from those at extraadrenal locations. We therefore use the term paraganglioma here for both extraadrenal and adrenal tumors.

Most paragangliomas are sporadic or are not associated with any obvious familial syndrome. However, among the tumors that appear to be sporadic, between 12 and 24% have a hereditary basis, involving mutations of five different genes: the rearranged during transfection protooncogene, the von Hippel Lindau gene, the neurofibromatosis type 1 gene, and the succinate dehydrogenase enzyme subunits B (SDHB) and D (3, 4).

Mutations of genes encoding SDHB and SDHD are the most recently identified genetic causes of paraganglioma (5, 6). Mutations of both genes are associated with relatively high rates of extraadrenal compared with adrenal tumors, but SDHB mutations appear to be associated with more aggressive tumor behavior and a higher rate of malignancy (4, 7, 8, 9, 10, 11). In two separate studies, malignant disease was found in 38 and 83% of patients with tumors associated with germline SDHB mutations (4, 8, 10). These are much higher rates, compared with catecholamine-producing tumors due to other mutations or in patients with sporadic adrenal paragangliomas in whom rates of malignancy are less than 10% (12, 13, 14).

The above differences suggest that substantial numbers of malignant catecholamine-producing tumors may be due to germline mutations of the SDHB gene. We therefore examined the frequency of germline mutations of the SDHB gene in patients with malignant disease arising from adrenal and extraadrenal paragangliomas.

	Patients and Methods

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Patients

Blood samples for SDHB mutation analysis were collected prospectively for purposes of genetic testing from 44 consecutive patients with malignant paraganglioma referred to the National Institutes of Health Clinical Center between July 2000 and September 2005. Most patients (30 of 44) had a previous history of the tumor and were referred because of the presence or suspicion of recurrent or malignant disease. The others were diagnosed with malignant disease as part of their first presentation with the tumor. Importantly, patients had not undergone mutation testing before referral, were not related, and were not referred because of suspicion of hereditary disease, although in one patient the clinical history revealed a father with a previous tumor.

Malignant disease was diagnosed based on the presence of metastases at sites in which chromaffin tissue is normally absent (e.g. liver, lungs, bones, and lymph nodes). Several patients had multiple occurrences of adrenal or extraadrenal paragangliomas, diagnosed either simultaneously or at different times. Particular care was taken in these patients to ensure that multifocal or locally recurrent disease was not confused with malignant disease.

Clinical information collected included age at first diagnosis of disease, location of the primary tumor, interval between diagnosis of the primary tumor and metastases, locations of metastases and recurrent or multiple tumors, the interval between diagnosis of the primary and of metastatic disease, length of survival after diagnosis of metastatic disease, and plasma concentrations of catecholamines and metanephrines.

The study was carried out under an institutional review board approved protocol compliant with international guidelines. Written informed consent was obtained from all patients.

SDHB sequence analysis

Genomic DNA was extracted from whole blood using a commercially available kit (Puregene DNA purification kit; Gentra Systems Inc., Minneapolis, MN), according to the manufacturer’s instructions. PCR-based bidirectional sequencing of the eight coding exons and adjacent intronic regions as well as portions of the 5'-untranslated and 3'-untranslated regions of the SDHB gene was performed by the Division of Molecular Diagnostics at the University of Pittsburgh Medical Center (Pittsburgh, PA) under a commercial research contract. The potential significance of sequence variants identified was based on American College of Medical Genetics criteria (categories 1–5) as well as prior publications and updated information from correspondence with researchers actively investigating SDHB and SDHD gene variants worldwide. For purposes of this paper, the term mutation is used to describe a nucleotide sequence variant expected to cause disease by virtue of protein truncation, abnormal splicing, or missense substitution previously associated with disease.

Biochemical analysis

Measurements of plasma catecholamines and metanephrines were by liquid chromatography with electrochemical detection (15, 16).

Statistical analysis

Differences between groups were compared by ², the Student t test, or ANOVA with Scheffé’s post hoc test where appropriate. For biochemical test results, statistical analyses were performed on data normalized by logarithmic transformation as established elsewhere (17).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Pathogenic SDHB mutations, including three novel and seven previously described variants (18), were detected in 13 patients (Table 1). Mutations included the well-known p.Arg46X mutation in two patients; the p.Cys196Tyr mutation in two patients; the IVS1 + 1G>T mutation in two patients; and IVS3 + 1G>A, IVS3 + 2T>A, p.Gly96Asp, p.Ile127Ser, p.Pro131fs, and p.Arg230His mutations, each detected in one patient. A previously undescribed two-nucleotide deletion frameshift variant (p.Glu228fs) in a single patient was considered pathogenic, as were two previously unreported variants at positions 1 and 2 of the SDHB intron 3 splice site (IVS3 + 1G>A, IVS3 + 2T>A). Four of the above patients also harbored previously described benign polymorphisms: p.Ser100Ser (patient 5), p.Ala6Ala (patient 7), IVS2–36T>G (patients 7 and 11), and IVS2 + 33G>A (patient 12).

The remaining 26 patients either had no SDHB mutations detected (n = 19) or were found to have previously recognized neutral polymorphisms (n = 7). These polymorphisms included the common p.Ala6Ala variant and IVS2–36T>G in three patients, the p.Ser163Pro variant in two patients, and IVS2 + 35G>A and IVS2 + 33G>A each in one patient. One patient with the p.Ala6Ala variant and IVS2–36T>G also had a 7/9 copy CTT trinucleotide repeat in the IVS4 splice acceptor region.

Among all patients with metastatic disease, the frequency of SDHB mutations ranged from 30% (13 of 44) to 41% (18 of 44), the former frequency reflecting inclusion of only those patients with established pathogenic mutations and the latter higher frequency reflecting additional inclusion of the five patients with possibly pathogenic variants.

There was no difference in age at first presentation of disease between patients with and without SDHB mutations (Table 2). However, proportions of patients with primary tumors (i.e. original tumors from which metastases developed) at extraadrenal vs. adrenal sites differed significantly (P = 0.018) according to the presence of the mutation. Among the 13 patients with SDHB mutations, 12 (92%) had primary tumors at extraadrenal locations, compared with 13 of 24 patients (54%) without SDHB mutations in which the adrenal vs. extraadrenal location of the primary tumor could be firmly established. Thus, the frequency of SDHB mutations among patients with malignant disease due to a primary extraadrenal tumor ranges from 48% (12 of 25) to 55% (16 of 29), the former frequency reflecting inclusion of only those patients with established pathogenic mutations and the latter higher frequency reflecting additional inclusion of the four patients with possibly pathogenic variants and extraadrenal primary tumors.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Our study is the first to establish that mutations of the SDHB gene are responsible for about half of all malignancies originating from extraadrenal paragangliomas. These data extend recent findings by Amar et al. (4), who carried out germline mutation testing in 314 patients with adrenal and extraadrenal paragangliomas, including 52 with malignant disease. Pathogenic mutations of the SDHB gene were identified in 15 of those latter patients (29%) (4). Our study yielded an almost identical frequency (30%).

With one exception, our examination of clinical characteristics of patients with and without SDHB mutations revealed no clear influence of the mutation on disease presentation, including surprisingly age at first diagnosis of disease. The exception was the finding that 92% of patients with an SDHB mutation had metastases arising from an extraadrenal rather than an adrenal tumor, compared with 54% of patients without evidence of the mutation. This finding is not unexpected, given previous findings of a high frequency of extraadrenal paragangliomas in patients with SDHB mutations (3, 8, 10). Nevertheless, consideration of the adrenal vs. extraadrenal nature of the primary tumor in a patient with malignant disease has important implications for the likelihood of an SDHB mutation. Whereas the chance of an SDHB mutation in a patient with malignant disease overall is a little over 1 in 4, that chance increases to almost 1 in 2 if the original primary tumor can be identified to have an extraadrenal location and decreases to less than 1 in 6 if the primary tumor has an adrenal location. Consideration of the adrenal or extraadrenal source of the metastases in a patient with malignant disease therefore has considerable impact on the likelihood of an SDHB mutation and the justification for mutation testing.

In addition to known pathogenic SDHB mutations, we detected several previously identified neutral polymorphisms and several novel SDHB variants, which could be pathogenic. Because none of these variants could be linked to disease in family members and without functional studies or a large reference population, a pathogenic role of those novel variants could not be confirmed. It nevertheless seems likely that the frequency of pathogenic SDHB mutations in patients with malignant disease found here is an underestimate of the true frequency. Another factor favoring underestimation of the frequency of SDHB mutations is that DNA sequencing approaches, as used here and also by Amar et al. (4), do not allow detection of all pathogenic mutations, including recently described large germline deletions (19, 20).

What are the clinical implications of the present findings with regard to testing patients for SDHB mutations? Because our data are in close concurrence with those of Amar et al. (4), we support their recommendation that all patients with metastatic disease be offered testing for SDHB mutations and that such testing should receive priority over testing for other disease-associated genes. Furthermore, our study shows that testing for germline SDHB mutations is especially important in patients with metastases arising from an extraadrenal tumor. The invariably fatal outcome of paraganglioma-associated malignant disease is presently unlikely to be affected by finding an SDHB mutation, but such a finding may well have important implications for triage, screening, and medical management of other family members, specifically the detection of tumors in asymptomatic mutation-positive family members (11). Findings of the mutation in such family members may be important for establishing routine screening for pheochromocytoma, and the resulting early detection and tumor removal may prevent any subsequent development of a fatal malignancy.

	Acknowledgments

 
We thank Edwin Lai, Thanh-Truc Huynh, John Uhrmacher, and Priya Kaji for their technical assistance and Diana Benn, Anne-Paule Gimenez-Roqueplo, and Patricia Dahia for helpful discussions.

	Footnotes

 
This work was supported by the intramural program of the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Cancer Institute, National Institutes of Health.

Disclosure statement: the authors have nothing to disclose.

First Published Online August 15, 2006

Abbreviation: SDHB, Succinate dehydrogenase enzyme subunit B.

Received February 23, 2006.

Accepted August 3, 2006.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/11/4505    most recent Author Manuscript (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 Brouwers, F. M. Articles by Pacak, K. Search for Related Content PubMed PubMed Citation Articles by Brouwers, F. M. Articles by Pacak, K. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Substance via MeSH Medline Plus Health Information Genetic Testing Related Collections Adrenal and Hypertension Endocrine Oncology