Sarah R. McWhinney

BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

Cisplatin, carboplatin, and oxaliplatin anticancer drugs are commonly used to treat lung, colorectal, ovarian, breast, head and neck, and genitourinary cancers. However, the efficacy of platinum-based drugs is often compromised because of the substantial risk for severe toxicities, including neurotoxicity. Neurotoxicity can result in both acute and chronic debilitation. Moreover, colorectal cancer patients treated with oxaliplatin discontinue therapy more often because of peripheral neuropathy than tumor progression, potentially compromising patient benefit. Numerous methods to prevent neurotoxicity have thus far proven unsuccessful. To circumvent this life-altering side effect while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-based biomarkers are under way. In this review, we detail findings from the current literature for genetic markers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy. These data have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy.

Familial Gastrointestinal Stromal Tumors and Germ-Line MutationsTo the Editor: Gastrointestinal stromal tumors may be sporadic or inherited in an autosomal dominant manner, alone or as a component of a syndrome associated with other tumors, such as in the context of neurofibromatosis type 1. 1 We have described seven male and five female patients (median age, 23 years) from five unrelated families who had both gastrointestinal stromal tumors and paragangliomas.Susceptibility to the tumors was inherited in an apparently autosomal dominant manner, with incomplete penetrance. 2 This condition has been referred to as "the dyad of paraganglioma and gastrointestinal stromal tumors" or the "Carney-Stratakis syndrome" (or "Carney-Stratakis dyad"). 3Germ-line mutations of the genes encoding succinate dehydrogenase subunits B, C, and D (SDHB, SDHC, and SDHD) have been described in inherited paraganglioma and pheochromocytoma 4 but not in familial gastrointestinal tumors.The family history of a kindred with multiple paragangliomas and a germ-line SDHB mutation included a person with a gastrointestinal stromal tumor, 5 but neither blood nor tissue specimens from this patient were studied for SDHB abnormalities.We identified six germ-line SDHB, SDHC, and SDHD mutations in patients with the dyad (Fig. 1).Gastrointestinal stromal tumors from the patients showed allelic losses around the chromosomal loci of the succinate dehydrogenase subunit.The patients did not have mutations of KIT or the gene for platelet-derived growth factor receptor alpha (PDGFRA), which have been associated with gastrointestinal tumors. 1 We conclude that familial gastrointestinal stromal tumors may be caused by mutations of the succinate dehydrogenase subunit genes SDHB, SDHC, and SDHD, and abdominal paragangliomas associated with gastrointestinal tumors may be caused uniquely by SDHC mutations.