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.

中文翻译：

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Nras 和 Braf 突变小鼠黑色素瘤模型中的 UVB 诱变有所不同。

BRAF突变黑色素瘤比NRAS突变黑色素瘤更有可能出现在免受慢性阳光损伤的解剖位置。我们假设肿瘤位置的这种差异是BRAF和NRAS突变黑素细胞对紫外线 (UV) 介导的致癌作用不同敏感性的结果。我们通过比较突变Braf杂合子或突变Nras纯合子小鼠模型中单一新生儿、紫外线 AI（UVA；340-400 nm）或紫外线 B（UVB；280-390 nm）暴露的致突变后果来测试这一假设。UVB（而非 UVA）加速了肿瘤的发生，并且产生的黑色素瘤含有影响 MAP3K1 的 RING 结构域和 Filamin A 的肌动蛋白结合结构域的反复突变。来自 UVB 照射的Braf突变小鼠的黑色素瘤平均单核苷酸数量是其两倍变体和二嘧啶变体的数量是来自类似照射的Nras突变小鼠的肿瘤的五倍。在 UVB 加速肿瘤中发现的突变特征反映了与人类皮肤癌相关的 COSMIC 特征，并且在Braf突变型小鼠黑色素瘤中比Nras突变型小鼠黑色素瘤更为突出。这些数据表明，单次 UVB 暴露会对致癌 Braf 驱动的小鼠肿瘤产生更大的突变负担。