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| Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas |
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| Author(s): Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Van Kien PK, Corvol P, Plouin PF, Jeunemaitre X |
| Source: CANCER RESEARCH Volume: 63 Issue: 17 Pages: 5615-5621 Published: SEP 1 2003 |
| Times Cited: 129 References: 31 |
| Abstract: Germ-line mutations in the genes encoding succinate dehydrogenase complex subunits B (SDHB) and D (SDHD) have been reported in familial paragangliomas and apparently sporadic phaeochromocytomas (ASP), but the genotype-phenotype relationships of these mutations are unknown. Eighty-four patients (all but 2 followed up for 8.8 +/- 5.7 years) with ASP (57 with adrenal tumors, 27 with extra-adrenal, multiple, malignant, or recurrent tumors) were screened for the major susceptibility genes for phaeochromocytoma (RET, VHL, SDHD, and SDHB). Thirty-three tumors were available for molecular analysis, enzyme assays, and immunohistochemistry. No (0%) RET and 2 (2.4%) VHL mutations were detected. Only two coding single nucleotide polymorphisms in the SDHD gene (G12S and H50R) were found in 6 patients (7%). Conversely, six deleterious mutations in the SDHB gene were identified in 8 patients (9.5%). Ectopic site and recurrence or malignancy were strongly associated with SDHB mutations (7 of 8, 87%, versus 20 of 76, 26%; P = 0.001). Somatic DNA analysis indicated a loss of heterozygosity at chromosome 1p36 (SDHB locus) in 16 of 33 cases (48%). A loss of heterozygosity at the SDHB locus was found in all tumors with SDHB mutation, and assays of respiratory chain enzymes showed a complete loss of complex II catalytic activity. The vascular architecture of tumors with SDHB mutations displayed features typical of malignancy. These data strongly suggest that SDHB gene is a tumor suppressor gene and that the identification of germ-line mutations in SDHB gene in patients with ASPs should be considered as a high-risk factor for malignancy or recurrence. |
| Document Type: Article |
| Language: English |
| Reprint Address: Gimenez-Roqueplo, AP (reprint author), Hop Europeen Georges Pompidou, Dept Mol Genet, AP HP, 20-40 Rue Leblanc, F-75015 Paris, France |
Addresses:
1. Hop Europeen Georges Pompidou, Dept Mol Genet, AP HP, F-75015 Paris, France
2. Hop Europeen Georges Pompidou, Serv Hypertens Arterielle, AP HP, F-75015 Paris, France
3. Hop Necker Enfants Malad, INSERM U393, Paris, France
4. Coll France, INSERM, U36, F-75231 Paris, France |
| Publisher: AMER ASSOC CANCER RESEARCH, PO BOX 11806, BIRMINGHAM, AL 35202 USA |
| Subject Category: Oncology |
| IDS Number: 722XD |
| ISSN: 0008-5472 |
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