Malinoc A, Sullivan M, Wiech T, et al.. Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3

Department of Nephrology and General Medicine Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
Endocrine Related Cancer (Impact Factor: 4.81). 02/2012; 19(3):283-90. DOI: 10.1530/ERC-11-0324
Source: PubMed


The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel-Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA-D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European-American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.

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    ABSTRACT: About one third of all patients with a pheochromocytoma are carriers of germ line mutations of 1 of the 10 susceptibility genes. Thus, these patients can be diagnosed and classified with specific tumor syndromes. This group is composed of the entities of multiple endocrine neoplasia type 2 (MEN2) due to mutations in the RET gene, von Hippel-Lindau disease (VHL, VHL gene), the paraganglioma syndromes types 1-4 (PGL1-4) due to mutations of the genes SDHD, SDHAF2, SDHC, SDHB, neurofibromatosis type 1 (NF1) due to mutations of the NF1 gene and familial pheochromocytoma syndromes due to mutations of the SDHA, TMEM127 and MAX genes. Patients with hereditary pheochromocytomas run a lifelong risk of relapse of pheochromocytoma. In addition extraparaganglial tumors are frequent and include medullary thyroid carcinoma in MEN2 or renal cancer or neuroendocrine pancreatic cancer as well as hemangioblastomas of the retina and the central nervous system in VHL. Furthermore, renal cancer may be associated with PGL4 and PGL3. In conclusion, molecular genetic screening is essential for the diagnosis of pheochromocytoma-associated cancer syndromes and is thus the cornerstone for successful lifelong preventive medicine of such patients and their relatives.
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    ABSTRACT: The genes for the succinate dehydrogenase (SDH) subunits SDHA, SDHB, SDHC and SDHD are encoded in the autosome. The proteins are assembled in the mitochondria to form the mitochondrial complex 2, a key respiratory enzyme which links the Krebs cycle and the electron transport chain. Thirty percent of phaeochromocytoma and paraganglioma (PHEO/PGL) are hereditary and perhaps as many as half of these familial cases are caused by germline mutations of the SDH subunits. Negative immunohistochemical staining for the SDHB subunit identifies PHEO/PGL associated with germline mutation of any of the mitochondrial complex 2 components and can be used to triage formal genetic testing of all PHEO/PGL for SDH mutations. PHEO/PGL associated with SDHA mutation also show negative staining for SDHA as well as SDHB.A unique subgroup of gastrointestinal stromal tumours (GISTs) are driven by mitochondrial complex 2 dysfunction. These SDH deficient GISTs can also be definitively identified by negative staining for SDHB and show distinct clinical and morphological features including frequent onset in childhood and young adulthood, gastric location, a tendency to multifocality, absence of KIT and PDGFRA mutations, a prognosis not predicted by size and mitotic rate and a tendency to indolent behaviour of metastases. Some of these SDH deficient GISTs are driven by classical SDH mutations, but the precise mechanisms of tumourigenesis in many (including those associated with the Carney triad) remain unknown. Germline SDHB mutation is associated with a newly recognised type of renal carcinoma which commonly but not always demonstrates distinctive morphology and can also be recognised by negative staining for SDHB.Immunohistochemistry for SDHB therefore has emerged as a useful tool to recognise these distinct neoplasias driven by mitochondrial complex 2 dysfunction and to triage formal genetic testing for the associated syndromes.
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