SDHB and SDHD Mutations in Malignant Pheochromocytomas. R. Klein, L. Jin, K. Rumilla, R. Lloyd. Dept Lab Medicine & Pathology, Mayo Clinic, Rochester, MN.
   Background: Germline mutations in the genes encoding the B (SDHB) and D (SDHD) subunits of the heterotetrameric protein succinate dehydrogenase (mitochondrial complex II) are important causes of inherited and apparently sporadic paragangliomas. Mutations in SDHB appear to be found more frequently in association with extra-adrenal and malignant pheochromocytomas, while mutations in SDHD are more often identified in benign head and neck paragangliomas. In an effort to further investigate the role of SDHB and SDHD in apparently sporadic malignant intra- and extra-adrenal pheochromocytomas, we screened a series of tumors for mutations in the SDHD and SDHB genes. Materials and Methods: Mutation testing was performed on DNA extracted from formalin fixed, paraffin embedded tumor and adjacent normal tissue by PCR amplification and direct sequencing of the coding regions and intron-exon junctions of the SDHB and SDHD genes. Results: Among 17 extra-adrenal pheochromocytomas with proven metastatic disease, 4 nonsense, 1 splice site, 1 insertion causing a frameshift, and 3 probable missense mutations were found in SDHB. No mutations were detected in SDHD. Mutations in SDHD and SDHB were not identified in 9 malignant intra-adrenal pheochromocytomas. The identical SDHB mutation was detected in DNA extracted from accompanying normal tissue for each of the 7 cases on which this analysis was performed. Conclusions: Germline mutations in SDHB are common in patients with malignant extra-adrenal pheochromocytomas, while SDHD mutations rarely occur. The disparate mutational spectra in malignant intra- and extra-adrenal pheochromocytomas may reflect differences in tumor biology.