Summary of Study ST002709

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.


This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002709
Study TitleFH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer
Study SummaryThe 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.
University of California, Los Angeles
DepartmentBiological Chemistry
LaboratoryHeather Christofk
Last NameMatulionis
First NameNedas
Address615 Charles E Young Dr S, BSRB 354-05
Phone(310) 206-0163
Submit Date2023-05-15
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2023-06-12
Release Version1
Nedas Matulionis Nedas Matulionis application/zip

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Combined analysis:

Analysis ID AN004391
Analysis type MS
Chromatography type HILIC
Chromatography system Thermo Vanquish
Column Merck SeQuant ZIC-pHILIC (150 x 2.1mm,5um)
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Units Peak Area