Fumarate Metabolic Signature for the Detection of Reed Syndrome in Humans

Richard Houghton,Eamonn R Maher,Stefano De Sanctis,Terri P Mcveigh,Ferdia A Gallagher,Anne Y Warren,Vasilis Kosmoliaptsis,Lee Mendil,Mary A Mclean,Ruth T Casey,Benjamin G Challis,Richard N Sandford

doi:10.1158/1078-0432.ccr-19-1729

Abstract

Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive in vivo detection of tumor succinate by proton magnetic resonance spectroscopy (1H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown. Magnetic resonance spectroscopy (1H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available. Here, we have demonstrated a proof of principle that 1H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation in vivo. This study demonstrates that in vivo detection of fumarate could be employed as a functional biomarker.

Highlights

In the past two decades, loss-of-function mutations in genes that encode components of the citric acid cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) have been demonstrated to predispose to a range of benign and malignant tumors [2,3,4,5,6]
Here, we have demonstrated a proof of principle that 1H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation in vivo
The clinical phenotype associated with FH mutations is hereditary leiomyomas and renal cell carcinoma syndrome (HLRCC) or Reed syndrome and comprises cutaneous and uterine leiomyomas, type 2 papillary renal cell carcinomas (RCC) [5, 8], and occasionally phaeochromocytomas/paragangliomas [6]

Summary

Introduction

In the past two decades, loss-of-function mutations in genes that encode components of the citric acid cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) have been demonstrated to predispose to a range of benign and malignant tumors [2,3,4,5,6]. The tumor risk for patients with SDHX mutations (SDHB, SDHD, SDHC, SDHA, and SDHAF2) varies according to the specific gene involved but the most frequent tumors overall are phaeochromocytomas, paragangliomas, head and neck paragangliomas, renal cell carcinomas (RCC), gastrointestinal stromal tumors, and rarely, pituitary tumors [7]. The clinical phenotype associated with FH mutations is hereditary leiomyomas and renal cell carcinoma syndrome (HLRCC) or Reed syndrome and comprises cutaneous and uterine leiomyomas, type 2 papillary RCCs [5, 8], and occasionally phaeochromocytomas/paragangliomas [6].

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Conclusion