Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma.

Autor:	Tandukar B; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA., Deivendran D; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA., Chen L; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Cruz-Pacheco N; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA., Sharma H; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA., Xu A; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Bandari AK; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Chen DB; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; School of Medicine, Case Western Reserve University, Cleveland, OH, USA., George C; Department of Dermatology, Erasmus MC, Rotterdam, Netherlands.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Dermatology, School of Medicine, Stanford University, Palo Alto, CA, USA., Marty A; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Institute of Physiology, University of Zurich, Zurich, Switzerland., Cho RJ; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA., Cheng J; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA., Saylor D; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA., Gerami P; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Arron ST; Peninsula Dermatology, Burlingame, CA, USA., Bastian BC; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA.; Department of Pathology, University of California San Francisco, San Francisco, CA, USA., Shain AH; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; Human Tumor Atlas Network (HTAN), National Cancer Institute, Bethesda, MD, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Dec 02. Date of Electronic Publication: 2024 Dec 02.
DOI:	10.1101/2024.07.23.604673
Abstrakt:	We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses of normal skin cells showed that most keratinocytes have remarkably low mutation burdens, despite decades of sun exposure, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens. These observations suggest that wild-type keratinocytes (i.e. without pathogenic mutations) are able to withstand high dosages of cumulative UV radiation, but certain pathogenic mutations break these adaptive mechanisms, priming keratinocytes for transformation by increasing their mutation rate. Mutational profiling of squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Surprisingly, actinic keratoses were often not related to their neighboring squamous cell carcinoma, indicating that collisions of unrelated neoplasms are common in the skin. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study catalogues the key events during the evolution of cutaneous squamous cell carcinoma.
Databáze:	MEDLINE
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