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 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.

Figure 1

The importance of the FH tumour suppressor gene in cutaneous leiomyoma. (a) Oncoplot highlighting the various ways FH is genetically altered in 42 cutaneous leiomyoma (cLM) samples from 27 patients. (b) The effect of mercaptopurine in FH-proficient and FH-deficient cells. The results of the clonogenic assay clearly demonstrate that addition of nucleosides can rescue the growth inhibitory effects induced by mercaptopurine, but only in FH-proficient cells (Fh1^fl/fl), not FH-deficient cells (Fh1^–/–CL1 and Fh1^–/–CL19). Statistical analysis was performed using a two-way Anova with Tukey multiple comparisons test (n = 4). cn-LOH, copy-neutral LOH; LOH, loss of heterozygosity; TMB, tumour mutational burden (shown as mutations/megabase)