Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Abstract

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified two tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as outstanding plasma biomarkers for early diagnosis (receiver operating characteristic area under curve (ROCAUC) = 0.98). These two molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Reporting on FH-deficient renal cell carcinoma using circulating succinylated metabolites

“…Suc-ado and suc-cys levels were elevated in the patients with FH-deficient RCC, in particular in those with stage III or IV tumors, by comparison with the other groups. Furthermore, blood levels of suc-ado and suc-cys in FH germline mutation carriers were indistinguishable from those in healthy adults, which is consistent with the notion that FH needs to be inactivated before the metabolites are overproduced ( 11 ).…”

“…The researchers identified several circulating metabolites that correlated with FH-mutant RCC and tumor size. While fumarate was elevated in the plasma of patients with FH-mutant RCC, its elevation was not specific to FH-deficient RCC ( 11 ). Indeed, circulating plasma fumarate is highly variable in healthy adults, reflecting the possible influence of diet and polymorphisms affecting FH expression in the general population ( 12 ).…”

“…In this issue of the JCI , Zheng, Zhu, and colleagues ( 11 ) close this knowledge gap by analyzing circulating plasma metabolites from patients with FH-deficient RCC. They identified two terminal metabolites, succinyl-adenosine (suc-ado) and succinic-cysteine (suc-cys), that were elevated in the plasma.…”

“…Indeed, circulating plasma fumarate is highly variable in healthy adults, reflecting the possible influence of diet and polymorphisms affecting FH expression in the general population ( 12 ). In contrast, suc-ado and suc-cys levels correlated with FH-deficient RCC and tumor burden ( 11 ).…”

“…Suc-ado and suc-cys blood levels increased proportionally with the growth of an FH-deficient PDX in mice but not with a ccRCC PDX. In addition, suc-ado and suc-cys levels acutely fell after resection of the FH-deficient tumors ( 11 ).…”