Journal of the National Cancer Institute Advance Access published online on August 26, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn254
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© The Author 2008. Published by Oxford University Press.
BRIEF COMMUNICATION |
Germline SDHB Mutations and Familial Renal Cell Carcinoma
Affiliations of authors: Cancer Research UK Renal Molecular Oncology Group, Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Edgbaston, Birmingham, UK (CR, ERW, PK, MRM, DA, FL, ERM); West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK (ERM)
Correspondence to: Eamonn R. Maher, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK (e-mail: e.r.maher{at}bham.ac.uk).
Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2) and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings 1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, 2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and 3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.
| CONTEXT AND CAVEATS Prior knowledge Germline mutations in SDHB, a gene encoding a subunit of the mitochondrial enzyme succinate dehydrogenase (SDH), have been found in patients with renal cell carcinoma (RCC) who had a personal or family history of pheochromocytoma or paraganglioma. It was not known whether mutations would be found in genes encoding subunits of SDH in people with evidence of a familial history of RCC but with no family history of these other cancers. Study design People for whom there was evidence of increased susceptibility to RCC (ie, family history or early age of diagnosis), but for whom there was no evidence of family history of pheochromocytoma or paraganglioma, were tested for germline mutations in genes encoding three subunits of SDH. Contribution Some people with evidence of inherited susceptibility to RCC but for whom there was no other evidence of another cancer susceptibility syndrome harbored germline mutations in SDHB. Implication Inherited mutations in SDHB may predispose individuals to RCC. Limitations The added risk of RCC conferred by mutations in SDHB and the benefit of screening for these mutations in patients with evidence of familial RCC remain to be determined. From the Editors
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Manuscript received February 8, 2008; revised June 10, 2008; accepted June 19, 2008.
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J Natl Cancer Inst 2008 100: 1193-1195.
J Natl Cancer Inst 2008 100: 1191.
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