The landscape of genetic alterations of <scp>UVB</scp> ‐induced skin tumors in <scp>DNA</scp> repair‐deficient mice
The landscape of genetic alterations of <scp>UVB</scp> ‐induced skin tumors in <scp>DNA</scp> repair‐deficient mice
复制标题
<scp>DNA</scp> 修复缺陷小鼠中 <scp>UVB</scp> 诱导的皮肤肿瘤的遗传改变
DOI：
10.1111/exd.14634
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发表时间：
2022
影响因子：
3.6
通讯作者：
Kunisada Makoto
中科院分区：
文献类型：
--
作者：
Yoshioka Ai;Nakaoka Hirofumi;Fukumoto Takeshi;Inoue Ituro;Nishigori Chikako;Kunisada Makoto
非黑色素瘤皮肤癌（NMSC）主要由紫外线（UV）诱导的体细胞突变引起，其特征是紫外线特征修饰。着色性干皮病A组（Xpa）基因敲除小鼠表现出极端紫外线诱导的光皮肤癌，并伴有光敏表型。我们对重复紫外线B （UVB）照射后的鳞状细胞癌（SCC）样本进行了全外显子组测序（WES），以研究xpaknockout和野生型小鼠之间体细胞突变景观的差异。尽管在小鼠中形成的肿瘤在一组相似的癌症相关基因中含有紫外线特征突变，但转录链不对称的模式却大不相同；xpaknockout和野生型小鼠的UV特征突变分别优先发生在转录链和非转录链上，反映了xpaknockout小鼠转录偶联核苷酸切除修复的缺陷。单次UVB暴露诱导肿瘤的WES序列时间点分析显示，致病突变inKras、Fat1和kmt2c可能是xpaknockout小鼠SCC发生和促进的驱动基因。此外，抗炎CXCL1单克隆抗体对xpaknockout小鼠肿瘤产生的抑制作用影响了体细胞突变的模式，其中转录链不对称被减弱，激活的信号转导从RAS/RAF/MAPK途径转移到PIK3CA途径。
Non‐melanoma skin cancer (NMSC) is mainly caused by ultraviolet (UV)‐induced somatic mutations and is characterized by UV signature modifications. Xeroderma pigmentosum group A (Xpa) knockout mice exhibit extreme UV‐induced photo‐skin carcinogenesis, along with a photosensitive phenotype. We performed whole‐exome sequencing (WES) of squamous cell carcinoma (SCC) samples after repetitive ultraviolet B (UVB) exposure to investigate the differences in the landscape of somatic mutations betweenXpaknockout and wild‐type mice. Although the tumors that developed in mice harboured UV signature mutations in a similar set of cancer‐related genes, the pattern of transcriptional strand asymmetry was largely different; UV signature mutations inXpaknockout and wild‐type mice preferentially occurred in transcribed and non‐transcribed strands, respectively, reflecting a deficiency in transcription‐coupled nucleotide excision repair inXpaknockout mice. Serial time point analyses of WES for a tumor induced by only a single UVB exposure showed pathogenic mutations inKras,Fat1, andKmt2c, which may be driver genes for the initiation and promotion of SCC inXpaknockout mice. Furthermore, the inhibitory effects on tumor production inXpaknockout mice by the anti‐inflammatory CXCL1 monoclonal antibody affected the pattern of somatic mutations, wherein the transcriptional strand asymmetry was attenuated and the activated signal transduction was shifted from the RAS/RAF/MAPK to the PIK3CA pathway.