Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.

Abstract

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 <i>FH</i> variants and additionally showed that somatic alteration of <i>FH</i> also drives cLM, with biallelic inactivation of <i>FH</i> being a frequent event. Treatment of <i>Fh1</i>-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 <i>Fh1</i>-proficient cells, suggesting that purine metabolism is a targetable vulnerability for <i>FH</i>-deficient cLMs.