Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

Abstract

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 for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and 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 in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this 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. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to 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 indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

Genetic Alterations in Pheochromocytoma and Paraganglioma

“…For the genes NF1, SDHD, SDHAF2, KIF1Bβ and VHL we found a significantly lower gene expression in samples with loss of one copy compared to those with normal copy number, which was particularly apparent for the NF1 gene (p<0.00001). A similar correlation between loss and gene expression has been observed for SDHD and SDHAF2 in VHL-associated pheochromocytomas (which often have loss of chromosome 11 214 ), but the pathological significance of this phenomenon is unknown 215 . We also analyzed the promoter region of the susceptibility genes for hypermethylation, which could represent another mechanism of gene inactivation, but we did not detect methylation in any of the genes.…”

Precision medicine in pheochromocytoma and paraganglioma: current and future concepts

“…Cluster 2 tumours display loss of 1p and 3q with high frequencies . The pathogenic mechanisms of 11p inactivation in VHL tumours and losses of 1p and 3q in cluster 2 PPGL remain to be determined .…”

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

“…By stratifying cases according to mutation and analyzing absolute ploidy, tumor cell fractions as well as position within the phylogenetic tree allowed temporal categorization and identification of events that occurred early in tumorigenesis (22). Loss of chromosome 1p (cluster 2 PPGL), oncogenic mutations (HRAS and RET), biallelic inactivation of 17q (NF1-mutated cases) as well as biallelic inactivation of VHL and loss of 11p (VHL-mutated cases) were obligate events occurring early in PPGL development (11,16,41). Differences in the chronological order of somatic driver mutations and obligate SCNA were not detectable, suggesting that both are needed for initial clonal expansion that occurred from a limited population of tumor cells.…”

“…Somatic copy-number alterations (SCNA) have also been described as exhibiting mutation-specific patterns (10). VHLassociated tumors are characterized by deletions of chromosomes 3 and 11, whereas those with RET and NF1 mutations display deletions of the short arm of chromosome 1 (10)(11)(12). NF1 tumors show frequent deletions of chromosome 17 and those with mutations in EPAS1 tumor show gains on chromosome 2 (10,(13)(14)(15).…”