Research Resource: Transcriptional Profiling Reveals Different Pseudohypoxic Signatures in SDHB and VHL-Related Pheochromocytomas

Abstract

The six major genes involved in hereditary susceptibility for pheochromocytoma (PCC)/paraganglioma (PGL) (RET, VHL, NF1, SDHB, SDHC, and SDHD) have been recently integrated into the same neuronal apoptotic pathway where mutations in any of these genes lead to cell death. In this model, prolyl hydroxylase 3 (EglN3) abrogation plays a pivotal role, but the molecular mechanisms underlying its inactivation are currently unknown. The aim of the study was to decipher specific alterations associated with the different genetic classes of PCCs/PGLs. With this purpose, 84 genetically characterized tumors were analyzed by means of transcriptional profiling. The analysis revealed a hypoxia-inducible factor (HIF)-related signature common to succinate dehydrogenase (SDH) and von Hippel-Lindau (VHL) tumors, that differentiated them from RET and neurofibromatosis type 1 cases. Both canonical HIF-1α and HIF-2α target genes were overexpressed in the SDH/VHL cluster, suggesting that a global HIF deregulation accounts for this common profile. Nevertheless, when we compared VHL tumors with SDHB cases, which often exhibit a malignant behavior, we found that HIF-1α target genes showed a predominant activation in the VHL PCCs. Expression data from 67 HIF target genes was sufficient to cluster SDHB and VHL tumors into two different groups, demonstrating different pseudo-hypoxic signatures. In addition, VHL-mutated tumors showed an unexpected overexpression of EglN3 mRNA that did not lead to significantly different EglN3 protein levels. These findings pave the way for more specific therapeutic approaches for malignant PCCs/PGLs management based on the patient's genetic alteration.

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

“…HIF-1a and HIF-2a (or sometimes exclusively HIF-2a) as well as several of their target genes have been shown to be overexpressed in SDH-and VHLmutated PCCs and PGLs (Pollard et al 2006, Lopez-Jimenez et al 2010). This suggests a critical role for HIF-1a and/or HIF-2a and hypoxia in these tumors, although their precise role in tumor development remains unclear.…”

La génétique des paragangliomes et des phéochromocytomes

“…On a longtemps considéré que seules 10 % de ces tumeurs étaient génétiquement déterminées, causées par des mutations constitutionnelles des gènes NF1 (neurofibromin) [2], RET (rearranged during transfection) [3] ou VHL (von Hippel Lindau) [4]. Après l'identification des gènes SDHD (succinate dehydrogenase complex, subunit D) [5], SDHC [6] et SDHB [7] [8,9], espagnoles [10] et françaises [11,12] ont révélé qu'après une classification non supervisée, chaque PGL/PCC ségrégeait selon son génotype dans l'un de deux clusters qui ont été définis. Le cluster 1 contenait les tumeurs SDHx (cluster 1A) et VHL (cluster 1B) alors que le cluster 2 regroupait les tumeurs liées aux gènes RET et NF1 (Figure 1).…”

Familial Catecholamine-Secreting Tumors - Three Distinct Families with Hereditary Pheochromocytoma

“…PGL1 is to be related to mutation in the SDHD gene, PGL2 to SDH5, PGL3 to mutation in SDHC and PGL4 to SDHB. SDH-related tumorigenesis is believed to associate with hypoxia-inducible factor (HIF)/angiogenesis pathway (Kantorovich et al, 2010;López-Jiménez et al,2010). In this chapter three families with different forms of familial pheochromocytoma has been shown.…”