title: Utility of the succinate: Fumarate ratio for assessing SDH dysfunction in different tumor types.
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.
  
  
  METHODS
  Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with knownSDHxmutation 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.affiliation: Clinical Chemistry, South Eastern Area Laboratory Services Pathology, Prince of Wales Private Hospital, Sydney, Australia.
authors.forename: Michael Jp
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.affiliation: Clinical Chemistry, South Eastern Area Laboratory Services Pathology, Prince of Wales Private Hospital, Sydney, Australia.
authors.forename: Talia
authors.initials: T
authors.lastname: Novos
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Benn
authors.affiliation: Clinical Chemistry, South Eastern Area Laboratory Services Pathology, Prince of Wales Private Hospital, Sydney, Australia; Department of Endocrinology and Diabetes, Prince of Wales Hospital, Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: White
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.
authors.forename: Trisha
authors.initials: T
authors.lastname: Dwight
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia; University of Sydney, Sydney, Australia.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Clifton-Bligh
keywords: Gastrointestinal stromal tumor; Mass spectrometry; Pheochromocytoma and paraganglioma; Renal cell carcinoma; Succinate dehydrogenase deficiency