Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3

Angelica Malinoc,Serdar Deger,Alexander Bosse,Michael M Hoffmann,Thorsten Wiech,Cordula Jilg,Charis Eng,Maren Sullivan,Joern Straeter,Kurt Werner Schmid,Hartmut P H Neumann,Gerd Rasp

doi:10.1530/erc-11-0324

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.

Highlights

Pheochromocytoma-related syndromes have contributed to our understanding of the pathogenesis of renal cell carcinomas (RCCs; Pavlovich & Schmidt 2004, Gill et al 2011b)
Major gains of knowledge regarding etiology and pathogenesis have come from hereditary RCC predisposition syndromes, chief of which is von Hippel–Lindau disease (VHL) disease caused by germline mutations of the VHL gene (Latif et al 1993, Zbar et al 1996, Neumann & Zbar 1997, Neumann et al 1998, Delahunt & Eble 2004, Grignon et al 2004, Maher et al 2011)
Germline mutations of SDHB have been found in patients with clear cell RCC (ccRCC) and RCC with a distinct solid histology (Vanharanta et al 2004, Ricketts et al 2008, Gill et al 2011a,b)

Summary

Introduction

Pheochromocytoma-related syndromes have contributed to our understanding of the pathogenesis of renal cell carcinomas (RCCs; Pavlovich & Schmidt 2004, Gill et al 2011b). The other, pheochromocytoma/paraganglioma syndrome (PGL), associated with germline succinate dehydrogenase (SDHB) mutations has been associated with increased risk of RCC. The most well-described disorder comprising both ccRCC and pheochromocytoma is VHL, a relatively common autosomal dominant heritable endocrine neoplasia syndrome, caused by germline mutations in the VHL tumor suppressor gene on 3p25–p26 (Lonser et al 2003). Heritable ccRCC associated with pheochromocytoma and paraganglioma has been described as a consequence of germline heterozygous mutations of the gene-encoding subunit B of the enzyme SDHB by at least two independent groups (Vanharanta et al 2004, Ricketts et al 2008).

Patients and methods

B Telomere

Discussion