1620 The cutaneous somatic landscape of prurigo nodularis

Prurigo nodularis (PN) is a debilitating chronic inflammatory skin disease that disproportionately affects Black patients. Little is known about genetic alterations in PN pathogenesis, especially as compared to atopic dermatitis (AD), a prototypical pruritic dermatosis. 54 lesional and non-lesional skin biopsies were prospectively collected from 17 PN and 10 AD patients. Whole-exome sequencing and matched somatic mutational analysis revealed that PN lesional skin harbors recurrent mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1, a regulator of cellular proliferation and a key driver of cutaneous squamous cell carcinoma (cSCC). Recurrent PN mutations absent in AD were enriched in the Notch-mediated and E2F transcriptional networks (q < 0.05). Comparison of PN with 83 public cSCC samples showed common mutations in NOTCH1 and FAT1, another driver of cSCC. Analysis of somatic copy-number alterations, corroborated by RNA-seq data, showed that recurrently deleted and downregulated (q < 0.05, log2fold-change < 0) genes in PN are significantly associated with neurotropic pathways (q < 0.05). Enrichment was driven by a recurrent (p < 0.05) 7q21 deletion only observed in Black PN patients, which affected SEM3A and neighboring semaphorin genes. Investigation into mutational processes revealed a UV-exposure signature, DBS1, that is predictive of PN (β = 0.78, p < 0.001) and itch intensity (β = 0.19, p = 0.003). Finally, functional validation via immunofluorescence revealed increased NOTCH1 expression in PN lesional skin fibroblasts (p = 0.018) and increased Notch signaling in PN lesional dermis (p = 0.010). This is the first and largest genomic study of PN to date. Our findings reveal novel insights into PN pathophysiology and uncover NOTCH1 as a potential therapeutic target.