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      Integrative Genetic Characterization and Phenotype Correlations in Pheochromocytoma and Paraganglioma Tumours

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          Abstract

          Background

          About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.

          Aim

          The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.

          Methods

          A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.

          Results

          Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations ( P = 0.022). SDHx/ VHL/ EPAS1 associated cases had higher norepinephrine output ( P = 0.03) and lower epinephrine output ( P<0.001) compared to RET/ NF1/ H-RAS cases.

          Conclusion

          Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.

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          Most cited references20

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          Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

          B E Baysal, R Ferrell, J Willett-Brozick … (2000)
          Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.
          Article 0 comments Cited 289 times – based on 0 reviews     Review now
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            Germ-line mutations in nonsyndromic pheochromocytoma.

            Hartmut Neumann, Birke Bausch, Sarah R. McWhinney … (2002)
            The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.
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              Mutations in SDHC cause autosomal dominant paraganglioma, type 3.

              S. Niemann, U Müller (2000)
              Nonchromaffin paragangliomas (PGLs) are usually benign, neural-crest-derived, slow-growing tumours of parasympathetic ganglia. Between 10% and 50% of cases are familial and are transmitted as autosomal dominant traits with incomplete and age-dependent penetrance.
              Article 0 comments Cited 167 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Sadashiva Karnik: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 22 January 2014
                Volume: 9
                Issue: 1
                Electronic Location Identifier: e86756
                Affiliations
                [1 ]Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
                [2 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [3 ]Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden
                Cleveland Clinic Lerner Research Institute, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JC PB. Performed the experiments: JC MN RM. Analyzed the data: JC MN PB. Contributed reagents/materials/analysis tools: MN DG PS PH PB. Wrote the paper: JC PB.

                Article
                Publisher ID: PONE-D-13-30598
                DOI: 10.1371/journal.pone.0086756
                PMC ID: 3899286
                SO-VID: b3d47ec6-2ed9-446a-b038-48b7bd205880
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 19 July 2013
                Date accepted : 13 December 2013
                Page count
                Pages: 11
                Funding
                The study was supported by grants from Swedish Cancer Society (PB), Selander Foundation (PB, PH, PS), Lions Cancer Foundation, Uppsala (JC, PH) and the Swedish state under the LUA/ALF agreement concerning research and education of doctors, (MN, id no. 76310). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Cancer Genetics
                Subject: Genetic Mutation
                Subject: Population Biology
                Subject: Epidemiology
                Subject: Genetic Epidemiology
                Subject: Medicine
                Subject: Clinical Research Design
                Subject: Epidemiology
                Subject: Endocrinology
                Subject: Neuroendocrinology
                Subject: Epidemiology
                Subject: Cancer Epidemiology
                Subject: Genetic Epidemiology
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Endocrine Tumors
                Subject: Adrenal Tumors
                Subject: Surgery
                Subject: Endocrine Surgery

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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