Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3.
ABSTRACT 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: The past 25 years have witnessed revolutionary changes in the care of patients with pheochromocytomas and extra-adrenal paragangliomas. Germline mutations of at least 13 genes are now associated with tumor development, a greater degree of hereditary susceptibility than for any other human neoplasm. Somatic mutations, either of the same genes or of several additional ones with closely related functions, are also increasingly recognized. Clinicians are now aware of the genetic implications of a pheochromocytoma or paraganglioma. All patients are therefore offered genetic testing and receive lifelong surveillance. Almost all of the mutated genes have well-described correlations with clinical and biochemical phenotypes. Tumors arising in patients with mutations of the SDHB gene have at least a 30 % chance of metastasizing and typically produce norepinephrine and/or dopamine. Assay of plasma-free metanephrines serves as a highly sensitive and specific biochemical screen for the presence of catecholamine-producing tumors, and the dopamine metabolite methoxytyramine serves as a useful marker for detecting minimally functional tumors or their metastases. New functional imaging techniques provide highly sensitive tumor localization. In addition to differential diagnosis, pathologists play new roles in helping to identify hereditary disease and guiding the sequence of genetic testing.Endocrine Pathology 12/2013; · 1.60 Impact Factor
Article: My life for pheochromocytoma.[Show abstract] [Hide abstract]
ABSTRACT: Extract: The fascination of hereditary tumor diseases, especially von Hippel-Lindau disease (VHL) and pheochromocytoma, has dominated my academic life for three decades. My background was the warm and rich atmosphere which gave me my parents, Colonel Joachim Neumann and Mechtild Zuckschwerdt, PhD, MA, descendent of an industrial family from Magdeburg. Together with 3 sisters and a brother, I spent my youth in Brunswick, Hamburg and Bonn with a classical education including Latin and Greek. I served 2 years in the artillery of the German army. From 1969 until 1974, I studied medicine at the Universities of Bonn and Heidelberg ...Endocrine Related Cancer 01/2014; · 5.26 Impact Factor
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ABSTRACT: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma (PCC)/ paraganglioma (PGL) tumors in SDH-x mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinico-pathological phenotype and even causal relatedness to SDH-x mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centres. SDHA/SDHB immunohistochemistry (IHC), SDH-x mutation analysis and loss of heterozygosity analysis of the involved SDH-x gene were performed on all tumors. A cohort of 348 tumors of unknown SDH-x mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas and adenomatoid tumors, was investigated by SDHB IHC.Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the wild-type allele, indicating bi-allelic inactivation of the germline mutated gene. Out of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.These findings strengthen the aetiological association of SDH-x genes with pituitary neoplasia, while provide evidence against a link between PTC and SDH-x mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDH-x alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.European Journal of Endocrinology 10/2013; · 3.14 Impact Factor