UVB mutagenesis differs in NRAS- and BRAF-mutant mouse models of melanoma

Abstract

It is difficult to discern the relative contributions of ultraviolet-A (UVA; 320-400nm) and ultraviolet-B (UVB; 280-320nm) radiation to human melanoma development. Here, we compared the tumorigenic consequences of a single UVA or UVB exposure in mouse models predisposed to Braf- or Nras-mutant melanoma. Exposures approximated the amount of UVA or UVB energy contained in ∼40 minutes of summer sunlight. While UVA accelerated melanoma onset in a subset of mice, UVB universally reduced tumor latency and induced gene mutations relevant to the human disease. Genomic analyses uncovered distinct mutational signatures specific to each UV spectrum. The UVB-specific signature was biased for mutations on the untranscribed DNA strand and closely mirrored mutational signatures enriched in human cutaneous melanoma. The UVA-specific signature mimicked SBS51, a mutational signature found in human uveal melanoma. Distinctions in the trinucleotide patterns of the UVA and UVB signatures suggest that cytosine deamination plays a key role in UVB-mediated melanomagenesis.

Cell‐intrinsic melanin fails to protect melanocytes from ultraviolet‐mutagenesis in the absence of epidermal melanin

“…Moreover, the role of epidermal melanin in protecting melanocytes from UV carcinogenesis is likely significant, possibly negating the detrimental effects of cell‐intrinsic pigment production. In prior experiments using the TpN mouse model, only one of 14 black mice (7%) “escaped” the effects of UV, whereas here, six of 17 black (35%) TpN mice showed delayed melanoma onset after irradiation (Bowman et al, 2021; Figure 1c). These “escapees” originated from different litters but could have arisen due to movement of the neonates during UV irradiation or the co‐inheritance of a select set of polymorphisms along with the Tyr c‐2j albino allele.…”

“…In this study we used a solar simulator equipped with a UVB bandpass filter, which produces a defined spectrum (Figure S3B). Our prior studies used a hand‐held device with UVB bulbs (Bowman et al, 2021; Hennessey et al, 2017). The spectrum of these bulbs contained ~8% UVC and ~50% UVA, which may promote further carcinogenicity and a higher penetrance of accelerated melanoma formation.…”

“…For example, UVB equally accelerated melanoma onset in black and albino HGF‐transgenic mice, while UVA enhanced melanoma formation only in the black transgenic mice (Noonan et al, 2012). Recent studies from our laboratory and others contradict this idea, showing that UVA has negligible effects on melanoma onset and mutational burden in pigmented GEMMs (Bowman et al, 2021; Viros et al, 2014). These observations highlight a need to better understand the ultimate impact of melanocyte‐intrinsic melanin on the mutational landscape and development of melanoma.…”

“…The TpN model mimics the expression of oncogenic NRAS in human melanocytic nevi and melanomas, and models p16 INK4a loss of function, which occurs in ~70% of these tumors (Bauer et al, 2007; Cancer Genome Atlas, 2015; Roh et al, 2015). UVB irradiation on postnatal Day 3 catches a portion of melanocytes in a transitory, non‐follicular position and accelerates the formation of melanomas with mutational patterns akin to those observed in the human disease (Bowman et al, 2021; Hennessey et al, 2017; Mukhopadhyay et al, 2016; Trucco et al, 2019; Viros et al, 2014). We crossed TpN mice to albino mice carrying an inactivating mutation in Tyrosinase ( Tyr c ) to produce litters containing black ( Tyr WT/WT ) and albino ( Tyr c/c ) animals on the same genetic background (C57BL/6J).…”

The OSUMMER lines: a series of ultraviolet-accelerated NRAS-mutant mouse melanoma cell lines syngeneic to C57BL/6

“…OSUMMER cells are derived from spontaneous melanomas that arise in Tyr::Cre-ER(T2) LSL-Nras ( TN ) mice expressing one of four distinct NRAS mutants: Q61R, Q61K, Q61L, or G13R, from the endogenous gene locus. Subjecting these mice to a single, neonatal dose of UV irradiation leads to the formation of tumors with mutational patterns analogous to those observed in human melanoma (Bowman et al, 2021). Through in vitro, genomic, and in vivo studies, we show that OSUMMER cells have diverse growth rates, mutational burdens, MEK inhibitor sensitivities, and predicted antigenicity.…”