These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%.
Recently, three more genes (SDHD, SDHB, and SDHC) which are all related subunits of the mitochondrial complex II have been identified to cause susceptibility to pheochromocytoma and/or paraganglioma.
Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025).
The proband was diagnosed with phaeochromocytoma at an early age following an unexpected hypertensive crisis and was found to be SDHB mutation-positive.
These findings suggest that although germline SDHB mutations are an important cause of phaeochromocytoma susceptibility, somatic inactivation of SDHB does not have a major role in sporadic neural crest tumours and SDHB is not the target of 1p36 allele loss in neuroblastoma and phaeochromocytoma.
Mutations in the SDHB (1p35-36) and SDHD subunits (11q23) give rise to the paraganglioma syndromes (PGL), namely PGL 4 and PGL 1, and generate paraganglioma and pheochromocytoma.
Finally, discovery of a shared activation of the hypoxic response in pheochromocytomas with mutations in VHL and SDH genes and uncovering of a common JunB-mediated apoptosis defect in the major hereditary groups of pheochromocytoma have provided a mechanistic basis for the clinical similarities between these distinct syndromes.
In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X.
Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone.
A question confronting clinicians is whether they should screen patients with apparently sporadic pheochromocytomas for unsuspected germline mutations of some or all of the seven genes known to cause hereditary paraganglioma or pheochromocytoma (NF1, VHL, RET, MEN1, SDHD, SDHC, and SDHB).
Although inactivation of VHL and SDHB/D may disrupt similar HIF-dependent and HIF-independent signaling pathways, their effects on target gene expression are not identical, and this may explain the observed clinical differences in PCC and associated tumors seen with germline VHL and SDHB/D mutations.
Paraganglioma syndrome includes head and neck paraganglioma and pheochromocytoma, and is classified according to the three susceptibility genes involved, SDHB, SDHC, and SDHD.
So far, germline mutations in five genes have been identified to be responsible for familial PHEOs: the von Hippel-Lindau gene, which causes von Hippel-Lindau syndrome, the RET gene leading to multiple endocrine neoplasia type 2, the neurofibromatosis type 1 gene, which is associated with von Recklinghausen's disease and the genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB, SDHD), which are associated with familial paragangliomas and PHEOs.
In this study, in agreement with previous works, we found HIF1 alpha to be moderately or highly stabilized in 67% (16/24) and 77% (48/62) of HLRCC tumors and SDHB/C/D paragangliomas (PGL) and pheochromocytomas (PHEO), respectively.