Journal
EXPERIMENTAL DERMATOLOGY
Volume 31, Issue 10, Pages 1607-1617Publisher
WILEY
DOI: 10.1111/exd.14634
Keywords
skin carcinogenesis; transcribed strand; UVB; whole genome sequencing; Xpa-deficient mice
Categories
Funding
- AMED [JP20ek0109488, JP20ek0109450h0001]
- Research Organization of Information and Systems (ROIS)
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) [19k08749]
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Non-melanoma skin cancer (NMSC) is primarily caused by UV-induced somatic mutations with distinct UV signature modifications. Xpa knockout mice show extreme sensitivity to UV-induced photo-skin carcinogenesis and exhibit a photosensitive phenotype. In this study, the differences in somatic mutation landscapes between Xpa knockout and wild-type mice were investigated after repetitive UVB exposure. We found that although the tumors in both types of mice had UV signature mutations in similar cancer-related genes, the pattern of transcriptional strand asymmetry differed significantly, indicating a deficiency in transcription-coupled nucleotide excision repair in Xpa knockout mice.
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 between Xpa knockout 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 in Xpa knockout and wild-type mice preferentially occurred in transcribed and non-transcribed strands, respectively, reflecting a deficiency in transcription-coupled nucleotide excision repair in Xpa knockout mice. Serial time point analyses of WES for a tumor induced by only a single UVB exposure showed pathogenic mutations in Kras, Fat1, and Kmt2c, which may be driver genes for the initiation and promotion of SCC in Xpa knockout mice. Furthermore, the inhibitory effects on tumor production in Xpa knockout 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.
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