title: Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas.
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.
  
  
  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.
  
  
  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.
authors: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors: Johan
authors: J
authors: Kugelberg
authors: Jenny
authors: J
authors: Welander
authors: Francesca
authors: F
authors: Schiavi
authors: Ambrogio
authors: A
authors: Fassina
authors: Martin
authors: M
authors: Bäckdahl
authors: Catharina
authors: C
authors: Larsson
authors: Giuseppe
authors: G
authors: Opocher
authors: Peter
authors: P
authors: Söderkvist
authors: Patricia L
authors: PL
authors: Dahia
authors: Hartmut P H
authors: HP
authors: Neumann
authors: Oliver
authors: O
authors: Gimm
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000209:etiology / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D005819:Genetic Markers; D060005:Genotyping Techniques; D006801:Humans; D019656:Loss of Heterozygosity; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010673:Pheochromocytoma / Q000209:etiology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D024101:Mitochondrial Proteins; C543341:SDHAF2 protein, human; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase