Year: 2026
Type: article
Abstract: Identifying the mutant genes that are selected during carcinogenesis is key to identifying candidates for intervention and understanding the processes that promote transformation. Here we applied two selection metrics to study the dynamics of mutational selection in a mouse model of ultraviolet light driven skin carcinogenesis in which multiple synchronous tumors develop in each animal. Sequencing normal skin and tumors over a time course revealed two genetic routes to squamous carcinoma. Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors. The remaining tumors carried other oncogenic mutants, including activating Kras mutations. However, other positively selected mutant genes lost their competitive advantage in heavily mutated epidermis and in tumors. We found ten mutant genes under negative selection in normal skin, one of which was also negatively selected in tumors. In addition one gene was negatively selected in tumors but not normal skin. We conclude that analysing selection in normal tissue alongside tumors may resolve the dynamics of selection in carcinogenesis and refine the identification of cancer drivers.
Source: Communications Biology
Institutions: Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Wellcome Sanger Institute, European Bioinformatics Institute, German Cancer Research Center, University of Lausanne, University Medical Center of the Johannes Gutenberg University Mainz, Addenbrooke's Hospital, University Hospital Zurich, Johannes Kepler University of Linz, University College London, Hutchison/MRC Research Centre
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: Wellcome Sanger Institute Quinquennial Review 2021-2026, G3715085817, G5150074400, Wellcome Sanger Institute Quinquennial Review 2021-2026, G544591541, G5472151112, Control of skin responses to UV and skin carcinogenesis by the nuclear receptors PPARs, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G8685439927
OpenAlex ID: W7123358148