Utility of the succinate: Fumarate ratio for assessing SDH dysfunction in different tumor types☆

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Abstract

Objective

Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinate:fumarate in FFPE specimens.

Patients and methods

Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate.

Results

FFPE samples showed higher succinate:fumarate ratios in SDH-deficient PPGLs compared to SDH-sufficient PPGLs. Similarly, a higher succinate:fumarate ratio was able to distinguish SDH-deficient GISTs and RCCs from their SDH-sufficient counterparts with great selectivity. Interestingly, the cut-off value of the succinate:fumarate ratio was two-folds greater in RCCs than GISTs.

Conclusion

Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.

Related collections

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The SDHA, SDHB, SDHC, SDHD genes encode the four subunits of succinate dehydrogenase (SDH; mitochondrial complex II), a mitochondrial enzyme involved in two essential energy-producing metabolic processes of the cell, the Krebs cycle and the electron transport chain. Germline loss-of-function mutations in any of the SDH genes or assembly factor (SDHAF2) cause hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC) through a mechanism which is largely unknown. Owing to the central function of SDH in cellular energy metabolism it is important to understand its role in tumor suppression. Here is reported an overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis. 2011 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Edward Kim

Journal

Journal ID (nlm-ta): Mol Genet Metab Rep

Journal ID (iso-abbrev): Mol Genet Metab Rep

Title: Molecular Genetics and Metabolism Reports

Publisher: Elsevier

ISSN (Electronic): 2214-4269

Publication date PMC-release: 30 December 2016

Publication date Collection: March 2017

Publication date (Electronic): 30 December 2016

Volume: 10

Pages: 45-49

Affiliations

[a ]Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

[b ]Clinical Chemistry, South Eastern Area Laboratory Services Pathology, Prince of Wales Private Hospital, Sydney, Australia

[c ]Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

[d ]Department of Endocrinology and Diabetes, Prince of Wales Hospital, Sydney, Australia

[e ]University of Sydney, Sydney, Australia

Author notes

[* ]Corresponding author at: Cancer Genetics, Level 9, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2152, Australia.Cancer GeneticsLevel 9Kolling Institute of Medical ResearchRoyal North Shore HospitalSt LeonardsNSW2152Australia edward.kim@ 123456sydney.edu.au

[1]

These authors contributed equally to the manuscript.

Article

Publisher ID: S2214-4269(16)30128-8

DOI: 10.1016/j.ymgmr.2016.12.006

PMC ID: 5219629

PubMed ID: 28070496

SO-VID: 1225d8ea-eb8a-4981-b64c-66507374ee80

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 17 October 2016

Date accepted : 17 December 2016

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