Summary of project PR001679

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, where it has been assigned Project ID PR001679. The data can be accessed directly via it's Project DOI: 10.21228/M8P71W This work is supported by NIH grant, U2C- DK119886.


Project ID: PR001679
Project DOI:doi: 10.21228/M8P71W
Project Title:FH variant pathogenicity promotes salvage pathway dependence in kidney cancer
Project Summary:The tricarboxylic citric acid cycle enzyme fumarate hydratase (FH) is a tumor suppressor. When lost in cells, its substrate fumarate accumulates to mM levels and drives oncogenic signaling and transformation. Germline alterations lead to an autosomal dominant condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to various benign tumors and an aggressive form of kidney cancer. FH alterations of unclear significance are frequently observed with germline testing; thus, there is an unmet need to classify FH variants by their cancer-associated risk, allowing for screening, early diagnosis and treatment. Here we quantify catalytic efficiency of 74 FH variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks purine biosynthesis, rendering FH-deficient cells more sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. Together, these findings suggest pathogenicity of many patientassociated FH variants and reveal nucleotide salvage as a targetable vulnerability in FHdeficient cancer cells.
Institute:University of California, Los Angeles
Department:Biological Chemistry
Laboratory:Heather Christofk
Last Name:Matulionis
First Name:Nedas
Address:615 Charles E Young Dr S, BSRB 354-05
Phone:(310) 206-0163

Summary of all studies in project PR001679

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)
(* : Contains raw data)
ST002709 FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer NCCFH1, UOK262, UTFHC1 University of California, Los Angeles MS 2023-06-12 1 24 Uploaded data (1.6G)*