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  • A relationship between SDH function and oxygen regulation has been suspected based on previous identification of increased expression of angiogenic factors in cases of SDH-mutant pheochromocytomas [[pgen-0010008-b09]]. Also, clinical similarities besides pheochromocytoma have been noted in families with germline mutations of VHL and SDHB [[pgen-0010008-b26]]. This is in agreement with our transcription results and biochemical data indicating that HIF1α is involved in this association. The bipartite transcription clustering of pheochromocytomas has thus provided an explanation for the link between two genetic subtypes of pheochromocytomas. We also showed that this distribution has high predictive value, as determined by the identification of previously undetected mutations in tumor samples segregating with the appropriate cluster. The successful distinction of tumors from Cluster 1 and Cluster 2 by SDHB immunostaining in our pilot series suggests that this may be developed into a new screening method to classify pheochromocytomas in one of two major categories that reflect the underlying genetic defect. Of interest, in a recent study, immunohistochemistry of head and neck paragangliomas with SDHB and SDHD mutations revealed similar suppression of SDHB, which was accompanied by morphologically abnormal mitochondria [[pgen-0010008-b27]]. This is in line with our results of catecholamine-secreting tumors and suggests that SDHB downregulation is a general marker of complex II dysfunction. This study also describes a number of sporadic head and neck paragangliomas with low SDHB staining; these tumors might correspond with Cluster 1 pheochromocytomas for which no detectable mutation was identified and that also appear to arise from disruption of related pathways. It remains to be tested whether the predominant hypoxic-angiogenic profile of pheochromocytomas with VHL and SDH mutations will render these tumors targets for antiangiogenic therapies. This will be particularly relevant for SDHB-mutant pheochromocytomas which have been suggested to be more prone to malignancy [[pgen-0010008-b10]].


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