title: 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.
authors.affiliation: Department of Nephrology and General Medicine Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Angelica
authors.initials: A
authors.lastname: Malinoc
authors.forename: Maren
authors.initials: M
authors.lastname: Sullivan
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Cordula
authors.initials: C
authors.lastname: Jilg
authors.forename: Joern
authors.initials: J
authors.lastname: Straeter
authors.forename: Serdar
authors.initials: S
authors.lastname: Deger
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Bosse
authors.forename: Gerd
authors.initials: G
authors.lastname: Rasp
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000368:Aged; D000483:Alleles; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human