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.3GOA (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.

Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma

“…4 Similarly, a few prior reports have identified RCCs with complete or partial absence of SDHB immunohistochemical staining 8,10 or RCCs in families with known SDH subunit gene mutations 4,9 that demonstrate other histologic appearances, including tumors resembling clear cell RCC, papillary RCC, sarcomatoid and unclassified RCCs. 4,[8][9][10] The significance of this occurrence remains incompletely understood. In at least some circumstances, renal tumors 9 and other neoplasms 10,35 occurring in patients with known germline SDH subunit mutations have been found to have normal immunohistochemical staining for SDHB, suggesting that they develop through mechanisms other than biallelic SDH subunit inactivation.…”

“…5,6 Many of the renal tumors that have been recognized to date in these patients exhibit distinctive morphology, characterized by sheets of uniform cells with eosinophilic or oncocytic cytoplasm that contain cytoplasmic vacuoles or flocculent inclusions. [5][6][7][8] However, renal cell carcinomas (RCCs) with other histologic appearances have been reported in patients with germline mutations of SDH subunit genes, 4,9 and a few RCCs of other histologic types have been found to be SDH-deficient in the absence of known germline gene mutation. 8,10 Nonetheless, experience with SDH-deficient RCC demonstrating this unique oncocytic histology remains very limited.…”

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

“…62 Further adding to those rare familial cases characterized by disparity between molecular genetic aberrations of a tumor suppressor gene and retention of protein expression, 63 one papillary renal cell carcinomas arising in a patient with a germline missense SDHC mutation (c.3G4A p.M1I) and harboring somatic loss of heterozygosity of the SDHC locus paradoxically displayed SDHB immunopositivity. 36 Taken together, SDHB immunohistochemistry and SDH-x genetic analysis should be viewed as complementary tests. In cases of strong clinical suspicion, follow-up mutational analysis should be considered despite retention of SDHB expression.…”

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…51,52 Another one was in SDHC (c.380A>G; p.His127Arg), and the last three were in SDHD (c.14G>A; p.Trp5*, c.149A>G; p.His50Arg, and c.274G>T; p.Asp92Tyr). 46,[53][54][55] Among these SDHD mutations, one resulted in a stop codon (p.Trp5*), which cannot be managed by the prediction tools we used but can be considered to Review be damaging because the mutation results in a severely truncated protein. This nonsense variant was identified in a patient suffering from Carney-Stratakis syndrome, with the PGL showing positive SDHB on IHC and the GIST presenting with a negative SDHB on IHC, potentially indicating two different second hit events in the SDHD gene.…”