The authors deserve commendation for focusing on an unmet medical need, their rational metabolomics approach, the mechanistic studies and assessment in mouse models, and their longitudinal analyses in a few patients. Additional studies will be required to assess the sensitivity and specificity as well as the clinical utility of suc-ado and suc-cys for the detection and management of FH-deficient RCC.

The data presented by Zheng, Zhu, and colleagues (11) suggest that suc-ado and suc-cys may be used to monitor treatment response and disease burden over time. Thus, these readily accessible blood biomarkers could complement routine imaging studies, and their utility deserves to be explored in prospective clinical trials.

Another setting in which circulating biomarkers of FH-deficient RCC would be useful is in the detection of subclinical disease. Biomarkers would be useful, for example, to ascertain whether there may be unappreciated subclinical disease after resection of an isolated primary tumor. However, the observation that suc-ado and suc-cys levels became undetectable in a patient who had an overt recurrence later on raises questions about the sensitivity of these metabolites to detect minimal residual disease. The same concern applies to the detection of undiagnosed FH-deficient RCC in patients with HLRCC.

Circulating biomarkers of FH-deficient RCC could also be helpful in the evaluation of small renal masses in the sporadic setting. Small renal masses are often followed with periodic surveillance scans to assess their growth over time, and biopsies are not always performed. However, if a tumor was determined to be FH-deficient, this would likely prompt early intervention. With the availability of reliable blood biomarkers, more customized approaches could be offered.

One particularly promising application is in the pathological diagnosis of sporadic FH-deficient RCC. Genetic testing is not routinely performed on sporadic RCC, and histological analyses are insufficient for diagnosis (14). The pathological diagnosis can be aided by IHC studies for FH and cysteine succination using an anti–S-(2-succino)-cysteine (anti-2SC) antibody. However, even with IHC studies, the diagnosis is not always straightforward (14, 15) and could be complemented by analyses of suc-ado and suc-cys levels in the blood.

Another question pertains to the specificity of suc-ado and suc-cys for FH-deficient RCC. Patients with germline FH mutations are also predisposed to uterine leyomyomas, which can reach a large size. How uterine leyomyomas would affect circulating levels of suc-ado and suc-cys is unclear from this study (11). Conversely, as the FH enzyme is a homotetramer, it is possible that some point mutants may exhibit dominant negative activity and substantially reduce FH activity in nontumor cells in patients with HLRCC. How this may impact suc-ado and suc-cys levels remains to be fully determined. In addition, the generation of suc-cys involves a renal tubular dipeptidase (DPEP1), and the impact of reduced renal mass (i.e., nephrectomy) and renal dysfunction on suc-cys levels remains unknown.

Moving forward, suc-ado and suc-cys should be evaluated in prospective trials before they are routinely incorporated in the clinic. Future studies should also address the added value of measuring both metabolites. The study by Zheng, Zhu, and colleagues (11) is a step in the right direction to identify clinically relevant biomarkers for a devastating subtype of kidney cancer.