RT Journal Article
SR Electronic
T1 UVB mutagenesis differs in <em>Nras</em>- and <em>Braf</em>-mutant mouse models of melanoma
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101135
DO 10.26508/lsa.202101135
VO 4
IS 9
A1 Robert L Bowman
A1 Rebecca C Hennessey
A1 Tirzah J Weiss
A1 David A Tallman
A1 Emma R Crawford
A1 Brandon M Murphy
A1 Amy Webb
A1 Souhui Zhang
A1 Krista MD La Perle
A1 Craig J Burd
A1 Ross L Levine
A1 A Hunter Shain
A1 Christin E Burd
YR 2021
UL https://www.life-science-alliance.org/content/4/9/e202101135.abstract
AB 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.