UVB mutagenesis differs in Nras- and Braf-mutant mouse models of melanoma.

Robert L Bowman,Rebecca C Hennessey,Brandon M Murphy,Craig J Burd,A Hunter Shain,Tirzah J Weiss,Emma R Crawford,Christin E Burd,David A Tallman,Amy Webb,Ross L Levine,Krista Md La Perle,Souhui Zhang

doi:10.26508/lsa.202101135

Abstract

BRAF-mutant melanomas are more likely than NRAS-mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS-mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single neonatal, ultraviolet-AI (UVA; 340-400 nm) or ultraviolet-B (UVB; 280-390 nm) exposure in mouse models heterozygous for mutant Braf or homozygous for mutant Nras Tumor onset was accelerated by UVB, but not UVA, and the resulting melanomas contained recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A. Melanomas from UVB-irradiated, Braf-mutant mice averaged twice as many single-nucleotide variants and five times as many dipyrimidine variants than tumors from similarly irradiated Nras-mutant mice. A mutational signature discovered in UVB-accelerated tumors mirrored COSMIC signatures associated with human skin cancer and was more prominent in Braf- than Nras-mutant murine melanomas. These data show that a single UVB exposure yields a greater burden of mutations in murine tumors driven by oncogenic Braf.

Highlights

The most common genetic subtypes of human melanoma, neuroblastoma RAS viral oncogene homolog (NRAS)- and v-Raf murine sarcoma viral oncogene homolog B (BRAF)-mutant, are enriched in different anatomical locations
These observations led us to speculate that BRAF-mutant melanocytes may acquire a higher burden of mutations than NRAS-mutant melanocytes exposed to a single ultraviolet light (UV) exposure
Tumors arising in most melanoma Genetically engineered mouse models (GEMMs), including our unirradiated TN and TB mice, are largely characterized by copy number alterations (CNAs) rather than single-nucleotide variant (SNV) (Hodis et al, 2012; Krauthammer et al, 2012; Wang et al, 2017; Zhang et al, 2016; Zloza et al, 2017)

Summary

Introduction

The most common genetic subtypes of human melanoma, neuroblastoma RAS viral oncogene homolog (NRAS)- and v-Raf murine sarcoma viral oncogene homolog B (BRAF)-mutant, are enriched in different anatomical locations. Despite the association of NRAS-mutant tumors with CSD skin, it is reported that UV signature lesions (C>T and CC>TT) are prevalent in a similar proportion of NRAS- and BRAF-mutant melanomas (The Cancer Genome Atlas, 2015). These observations led us to speculate that BRAF-mutant melanocytes may acquire a higher burden of mutations than NRAS-mutant melanocytes exposed to a single UV exposure. Genomic analyses of tumors from UV-treated Nras or Braf-mutant GEMMs have been reported (Viros et al, 2014; Mukhopadhyay et al, 2016; Trucco et al, 2019). A complete understanding of how different oncogenic drivers cooperate with environmental mutagens to promote transformation is lacking

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