Capturing the primordial Kras mutation initiating urethane carcinogenesis

• Published in: Nature communications Vol. 11; no. 1; pp. 1800 - 12
• Main Authors: Li, Siqi, MacAlpine, David M., Counter, Christopher M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 45/70; 631/67/395; 692/4028/67/395; Animals; Carcinogenesis; Carcinogens; Error correction; Ethyl carbamate; Female; Genome; Humanities and Social Sciences; Humans; K-Ras protein; Loci; Lung cancer; Male; Mammals - genetics; Mice; multidisciplinary; Mutagenesis; Mutation; Mutation - genetics; Mutation Rate; Next-generation sequencing; Organ Specificity; Protein Isoforms - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Ras protein; Science; Science (multidisciplinary); Sequence Analysis, DNA; Transcription; Tropism; Tumors; Urethane
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15660-8

The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q 61 L/R mutation in the gene Kras . Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to human cancers. To elucidate the principles underlying this RAS mutation tropism of urethane, we adapted an error-corrected, high-throughput sequencing approach to detect mutations in murine Ras genes at great sensitivity. This analysis not only captured the initiating Kras mutation days after urethane exposure, but revealed that the sequence specificity of urethane mutagenesis, coupled with transcription and isoform locus, to be major influences on the extreme tropism of this carcinogen. Why the carcinogen urethane causes only lung tumours driven by a specific oncogenic mutation in just one Ras gene in mice is unclear. Here, the authors capture mutations immediately after urethane exposure and show that the sequence specificity of mutagenesis, transcriptional status, and Ras genetic loci may all contribute to this specificity.