Abstract
The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/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.
Highlights
The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras
These finding indicate that RAS mutation tropism is a multifactorial process, which may inform similar RAS mutation patterns observed in human cancers
A barrier to detecting initiating mutations in Kras at the time they occur in vivo after urethane exposure is that the mutation rate of this carcinogen is well below the detection limit of next generation sequencing (NGS)
Summary
The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras. 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 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. 1234567890():,; Exposure of mice to the environmental carcinogen urethane primarily induces tumors in one organ (lung) with a single driver mutation in only one of the three Ras genes (Kras), at one position (Q61), with one substitution (L or R depending on the mouse strain)[1,2,3,4,5] This extreme RAS mutation tropism is rather remarkable considering that oncogenic Ras is well known to cause a host of cancers in the mouse beyond the lungs[6]. These finding indicate that RAS mutation tropism is a multifactorial process, which may inform similar RAS mutation patterns observed in human cancers
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