Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas
Johan Kugelberg
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorJenny Welander
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorFrancesca Schiavi
Familial Cancer Clinic, Veneto Institute of Oncology IRCCS, Padua, Italy
Search for more papers by this authorAmbrogio Fassina
Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
Search for more papers by this authorMartin Bäckdahl
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorCatharina Larsson
Department of Oncology-Pathology, Karolinska Institutet, CCK, Stockholm, Sweden
Search for more papers by this authorGiuseppe Opocher
Familial Cancer Clinic, Veneto Institute of Oncology IRCCS, Padua, Italy
Department of Medicine (DIMED), University of Padua, Padua, Italy
Search for more papers by this authorPeter Söderkvist
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorPatricia L. Dahia
Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA
Search for more papers by this authorHartmut P. H. Neumann
Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
Search for more papers by this authorCorresponding Author
Oliver Gimm
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Department of Surgery, County Council of Östergötland, 581 85 Linköping, Sweden
[email protected]Search for more papers by this authorJohan Kugelberg
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorJenny Welander
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorFrancesca Schiavi
Familial Cancer Clinic, Veneto Institute of Oncology IRCCS, Padua, Italy
Search for more papers by this authorAmbrogio Fassina
Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
Search for more papers by this authorMartin Bäckdahl
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorCatharina Larsson
Department of Oncology-Pathology, Karolinska Institutet, CCK, Stockholm, Sweden
Search for more papers by this authorGiuseppe Opocher
Familial Cancer Clinic, Veneto Institute of Oncology IRCCS, Padua, Italy
Department of Medicine (DIMED), University of Padua, Padua, Italy
Search for more papers by this authorPeter Söderkvist
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Search for more papers by this authorPatricia L. Dahia
Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA
Search for more papers by this authorHartmut P. H. Neumann
Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
Search for more papers by this authorCorresponding Author
Oliver Gimm
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Department of Surgery, County Council of Östergötland, 581 85 Linköping, Sweden
[email protected]Search for more papers by this authorJohan Kugelberg and Jenny Welander contributed equally to this work.
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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