Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas

Johan Kugelberg, Jenny Welander, Francesca Schiavi, Ambrogio Fassina, Martin Bäckdahl, Catharina Larsson, Giuseppe Opocher, Peter Söderkvist, Patricia L Dahia, Hartmut P H Neumann, Oliver Gimm

Research output: Contribution to journalArticle

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Abstract

Background: Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. Materials and methods: Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. Results and conclusions: LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.

Original languageEnglish (US)
Pages (from-to)724-732
Number of pages9
JournalWorld Journal of Surgery
Volume38
Issue number3
DOIs
StatePublished - Mar 2014

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Pheochromocytoma
von Hippel-Lindau Disease
Loss of Heterozygosity
Paraganglioma
Messenger RNA
Methylation
Mutation
Immunohistochemistry
Chromosomes, Human, Pair 11
Adrenal Medulla
Adrenal Cortex
Missense Mutation
Neoplasms
Chromosomes

ASJC Scopus subject areas

  • Surgery

Cite this

Kugelberg, J., Welander, J., Schiavi, F., Fassina, A., Bäckdahl, M., Larsson, C., ... Gimm, O. (2014). Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas. World Journal of Surgery, 38(3), 724-732. https://doi.org/10.1007/s00268-013-2373-2

Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas. / Kugelberg, Johan; Welander, Jenny; Schiavi, Francesca; Fassina, Ambrogio; Bäckdahl, Martin; Larsson, Catharina; Opocher, Giuseppe; Söderkvist, Peter; Dahia, Patricia L; Neumann, Hartmut P H; Gimm, Oliver.

In: World Journal of Surgery, Vol. 38, No. 3, 03.2014, p. 724-732.

Research output: Contribution to journalArticle

Kugelberg, J, Welander, J, Schiavi, F, Fassina, A, Bäckdahl, M, Larsson, C, Opocher, G, Söderkvist, P, Dahia, PL, Neumann, HPH & Gimm, O 2014, 'Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas', World Journal of Surgery, vol. 38, no. 3, pp. 724-732. https://doi.org/10.1007/s00268-013-2373-2
Kugelberg J, Welander J, Schiavi F, Fassina A, Bäckdahl M, Larsson C et al. Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas. World Journal of Surgery. 2014 Mar;38(3):724-732. https://doi.org/10.1007/s00268-013-2373-2
Kugelberg, Johan ; Welander, Jenny ; Schiavi, Francesca ; Fassina, Ambrogio ; Bäckdahl, Martin ; Larsson, Catharina ; Opocher, Giuseppe ; Söderkvist, Peter ; Dahia, Patricia L ; Neumann, Hartmut P H ; Gimm, Oliver. / Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas. In: World Journal of Surgery. 2014 ; Vol. 38, No. 3. pp. 724-732.
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abstract = "Background: Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 {\%} of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. Materials and methods: Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. Results and conclusions: LOH was found in more than 50 {\%} of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.",
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AU - Welander, Jenny

AU - Schiavi, Francesca

AU - Fassina, Ambrogio

AU - Bäckdahl, Martin

AU - Larsson, Catharina

AU - Opocher, Giuseppe

AU - Söderkvist, Peter

AU - Dahia, Patricia L

AU - Neumann, Hartmut P H

AU - Gimm, Oliver

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