Exploration of the mutational landscape of cutaneous leiomyoma confirms <i>FH</i> as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy
To comprehensively explore the mutational landscape of cutaneous leiomyoma (cLM) and identify candidate driver events, we performed a retrospective, multi-institutional, whole-exome sequencing and RNA sequencing study. We confirmed that a large proportion of patients with cLM have germline FH variants and additionally showed that somatic alteration of FH also drives cLM, with biallelic inactivation of FH being a frequent event. Treatment of Fh1-proficient and -deficient cell lines with the purine antagonist and chemotherapeutic agent, mercaptopurine, significantly decreased growth/colony formation; however, the addition of nucleosides was able to rescue only the Fh1-proficient cells, suggesting that purine metabolism is a targetable vulnerability for FH-deficient cLMs.
Authors
- Claire Hardy
- Désirée Schatton (ORCID: https://orcid.org/0009-0007-7554-8985)
- Thomas Brenn (ORCID: https://orcid.org/0000-0002-0089-0352)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Saamin Cheema (ORCID: https://orcid.org/0000-0002-5297-2042)
- Mark J. Arends (ORCID: https://orcid.org/0000-0002-6826-8770)
- Ian Vermes
- Martin Del Castillo Velasco‐Herrera (ORCID: https://orcid.org/0000-0001-5956-0211)
- Louise van der Weyden (ORCID: https://orcid.org/0000-0002-0645-1879)
- Steven D. Billings (ORCID: https://orcid.org/0000-0002-2278-5908)
- Marc Segarra‐Mondejar (ORCID: https://orcid.org/0000-0001-7376-7104)
- Victoria Offord (ORCID: https://orcid.org/0000-0003-3104-317X)
- Derek Frew (ORCID: https://orcid.org/0000-0002-0890-1415)
- Ingrid Ferreira (ORCID: https://orcid.org/0000-0002-4321-5250)
- Paul W. Harms (ORCID: https://orcid.org/0000-0002-0802-2883)
- Jacqueline Marcia Boccacino (ORCID: https://orcid.org/0000-0001-6813-5217)
- Nicolas de Saint Aubain
- Peter M. Ferguson (ORCID: https://orcid.org/0000-0002-8335-0406)
- Neil Rajan (ORCID: https://orcid.org/0000-0002-5850-5680)
- Kim Wong (ORCID: https://orcid.org/0000-0002-0984-1477)
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Alastair Droop (ORCID: https://orcid.org/0000-0001-7695-7480)
- David J. Adams (ORCID: https://orcid.org/0000-0001-9490-0306)
- Elizabeth Anderson
- David R A Jones
Institutions
- The University of Sydney (AU)
- Cleveland Clinic (US)
- Université Libre de Bruxelles (BE)
- University of Cologne (DE)
- University of Michigan (US)
- Royal Prince Alfred Hospital (AU)
- Western General Hospital (GB)
- Royal Victoria Infirmary (GB)
- Institut Jules Bordet (BE)
- Wellcome Sanger Institute (GB)
- Edinburgh Cancer Research (GB)
- Melanoma Institute Australia (AU)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Technical University of Munich (DE)
- Newcastle University (GB)
Publication Details
- Journal
- British Journal of Dermatology
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1093/bjd/ljae432
- Primary Topic
- Urinary and Genital Oncology Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Medical Research Council