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Distinct succinate modifying products are clinically diagnostic and prognostic biomarkers for fumarate hydratase deficient renal cell carcinoma

ABSTRACT:

Germline or somatic loss-of-function of fumarate hydratase (FH) predisposes patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for FH-deficient RCC, a competent method for early diagnosis and for early detection of recurrent and metastatic disease is an unmet clinical need. Currently, at best, an annual MRI scan is offered, though typically, MRI is used for symptomatic patients only. Therefore, finding specific and sensitive biomarkers suitable for routine and simple screens is crucial for improving the clinical outcome of these patients. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed a large-scale study of plasma metabolomics comparing FH-deficient RCC patients to no-tumor control individuals or to wildtype FH RCC patients. Our results indicated two fumarate-derived metabolites, succinyl-adenosine and succinic-cysteine, to be outstanding plasma biomarkers for early diagnosis, with a positive predictive value of more than 90%. Furthermore, using pre-clinical and biochemical studies, we identified the enzymatic mechanisms by which these biomarkers are produced in and around the tumors.

INSTRUMENT(S): Liquid Chromatography MS -, Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: Wu Xiaoyu

PROVIDER: MTBLS3628 | MetaboLights | 2022-08-12

REPOSITORIES: MetaboLights

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Project description:Purpose: Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated âtissue slice graftsâ (TSGs) as an improved tumorgraft model of RCC. Experimental Design: Cores of fresh RCC were precision-cut at 300-Î¼m and implanted under the renal capsule of RAG2-/-Î³C-/- mice. Engraftment rate, histology, biomarker expression, genetic fidelity and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a non-invasive method to measure tumor volume, and response to a targeted therapy was determined. Results: All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified non-invasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and VHL status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared to controls. Conclusions: The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared to other preclinical platforms. Three pairs of tissue slice graftes and parent tumors were included in the study. Tissue slice grafts and parent tumors were preserved in Allprotect tissue reagent (Qiagen, Valencia, CA) at -20Â°C prior to RNA extraction using an AllPrep DNA/RNA/Protein Mini Kit (Qiagen, Valencia, CA). The quality of RNA was determined using an Agilent 2100 Bioanalyzer (Agilent Biotechnologies, Santa Clara, CA). Microarray hybridization was performed using Illumina Human HT-12 v4 Beadchips (Illumina Inc., San Diego, CA) according to the manufacturerâs directions. Expression data was rank invariant normalized using BeadStudio software (Illumina Inc.).

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Distinct succinate modifying products are clinically diagnostic and prognostic biomarkers for fumarate hydratase deficient renal cell carcinoma

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