Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra
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Research Article Dermatology Genetics

Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis

Abstract

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.

Authors

Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D. Szeto, Anusha Kambala, Olusola O. Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M. Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M. Akiska, Davies M. Gage, Sarah Wheelan, Thomas Pritchard, Madan M. Kwatra, Yevgeniy R. Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G. Kwatra

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Figure 6

Somatic mutational differences between PN and AD.

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Somatic mutational differences between PN and AD. (A) Ten genes with the...
(A) Ten genes with the most frequent nonsynonymous somatic mutations in our AD cohort. (B) All nonsynonymous somatic mutations in AD and PN are ordered by their genomic locations on the x-axis and the corresponding VAF is shown on the y-axis. Variants with 0.3 or higher VAF are labeled with their gene name. (C) Histograms showing the frequency of nonsynonymous somatic variants on the x-axis at the corresponding VAF on the y-axis, in AD and PN. P value indicates the significant difference in means (Wilcoxon’s test). (D) Mutational diversity per sample using a normalized Shannon diversity index based on the VAF of somatic SNVs and indels in patients with PN and AD. One hypermutated AD sample was not excluded (see Methods). (E) The top mutated genes in our PN cohort are illustrated, with the corresponding relative frequency and percentage of alteration in AD and PN samples. (F) Rank order plot showing the somatic mutational burden per megabase across 17 patients with PN, 9 patients with AD, and all 33 cancers in The Cancer Genome Atlas cohort. Red lines indicate the median mutational burden. A dictionary for cancer symbols is included in Supplemental Table 3. (G and H) GO term enrichment results of 21 genes with nonsynonymous somatic mutations in at least 2 PN samples and no AD samples across 2 pathway databases. Terms with FDR-corrected P < 0.05 are colored in yellow. PN versus AD VAF and Shannon diversity were compared using Mann-Whitney U tests. Mutational burden across PN, AD, and TCGA cancers was compared using a Kruskal-Wallis test. GO enrichment analyses were performed using hypergeometric testing with FDR correction.