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Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.

ABSTRACT: Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

SUBMITTER: Vanharanta S

PROVIDER: S-EPMC1181902 | biostudies-literature | 2004 Jan

REPOSITORIES: biostudies-literature

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Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.

Vanharanta Sakari S Buchta Mary M McWhinney Sarah R SR Virta Sanna K SK Peçzkowska Mariola M Morrison Carl D CD Lehtonen Rainer R Januszewicz Andrzej A Järvinen Heikki H Juhola Matti M Mecklin Jukka-Pekka JP Pukkala Eero E Herva Riitta R Kiuru Maija M Nupponen Nina N NN Aaltonen Lauri A LA Neumann Hartmut P H HP Eng Charis C

American journal of human genetics 20031218 1

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SD ...[more]

PMID: 14685938

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Project description:Abstract Background: SDHB immunostaining can be used to functionally characterize SDH status in PCC and PGL. Assessing SDHB expression on tumors is inexpensive and can be used as an alternative to genetic testing. More importantly, assessment of SDHB expression can be of value in interpreting Variant of Unknown Significance (VUS) in SDH related genes. Objective: To investigate the effectiveness of SDHB immunostaining as an initial screening tool in identifying germline SDH mutations and the value of SDHB assessment in the clinical characterization of our patient cohort. Design: Prospective and retrospective analysis of 57 randomly selected patients with PCC and PGL from the year 1997 to 2018. Setting: In our institution on patients referred from London and South East England including Kent, Surrey and Sussex. Patients: Predominant Caucasian Population with diverse ethnicities. 57 patients - 34 patients (14M & 20F) with PGL and 25 with PCC (15M &10F). Age (mean: 41years at diagnosis with range 9-80 years). 2 patients had both PCC & PGL and multifocal PGLs were identified in few patients with SDHD and SDHB mutation. There were 65 tumors in total included in this study. Intervention: Resected tumor SDHB immunostaining with Sigma prestige antibodies (HPA002868 100UL - Anti-SDHB Rabbit monoclonal antibody) at a dilution of 1:1000. Genetic testing performed on predominant candidate genes. Main outcome measures: Concordance of SDHB loss of expression with presence of pathogenic mutation in candidate SDH genes. Secondarily, to explore SDHB immunostaining in our patient cohort with VUS in candidate genes. Results: SDHB immunostaining was negative in 22/23 tumors in patients with confirmed SDH mutation (false negative = 1 SDHB PCC where it was weak (+)). The staining was positive in 23/24 sporadic tumors, 10/11 VUS (in SDH, MAX and TMEM genes - both PCCs & PGLs), 2/2 PCCs in MEN-2, 2/2 PCCs in NF-1 and 2/3 PCCs in VHL. The negative immunostaining in 1 PGL with VUS in SDHB may imply lack of SDH enzyme activity and hence suggestive of a pathological mutation. The sensitivity is 96% and the specificity approaches 93% if the weak positive SDHB immunostaining with SDHD and VHL tumors were to be considered concordant. The concordance was 95% in the PGL group alone. Conclusions: SDHB immunostaining is a cost effective addition to PGL and PCC tumor characterization and performs with high sensitivity and specificity. SDH functional characterization has an important role in the management of patients who do not satisfy the current criteria for genetic testing (UK genetics testing directory for PCC/PGL). 18% of patients had VUS in a SDH related gene and we have found that SDHB immunostaining provided helpful information to inform follow-up and cascade screening decisions in this group.

Dataset Information

Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.

Publications

Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.

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