The dynamics of mutational selection in cutaneous squamous carcinogenesis

TL;DR

This study examines how mutations are selected during skin cancer development in mice, finding that only p53 mutants are consistently selected throughout the process.

Contribution

The study introduces a method to analyze mutational selection in normal tissue alongside tumors, revealing dynamic selection patterns in carcinogenesis.

Findings

Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors.

Ten mutant genes were under negative selection in normal skin, with one also negatively selected in tumors.

Other positively selected mutant genes lost their advantage in heavily mutated epidermis and tumors.

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.

Sequencing mutants in both normal skin and tumors that arise from it in a mouse model of ultraviolet light driven carcinogenesis reveals mutant selection changes as cancers develop. Only p53 mutants are selected throughout squamous carcinogenesis.

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