Capturing the primordial Kras mutation initiating urethane carcinogenesis.

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Oncogenic RAS mutations often display a tropism for different cancers, namely the frequency, isoform, position, or even substitution of RAS mutations can be quite specific for a given cancer.   As RAS mutations can be initiating, these mutation patterns presumably reflect the process of tumor initiation embedded in the genome of the resulting tumors (1).  We thus sought to elucidate how specific RAS mutations arise at tumor initiation.  Trying to backtrack to catch that one single, ostensibly random mutagenic event, in a single gene, in a single cell, decades before it manifests as cancer is challenging.  We therefore turned to the environmental carcinogen urethane to define the moment of tumor initiation, but also because this carcinogen nicely models the RAS mutation tropism of human cancers, primarily inducing lesions in one tissue (lung), initiated by one Ras isoform (Kras), with a mutation at one position (Q61) encoding one substitution, L or R depending on the mouse strain (2).  We still had one more hurdle to overcome- the extremely low frequency that urethane mutagenesis (2).  We thus adapted the ultra-sensitive technique of Maximum Depth Sequencing (MDS) used in microbiology (3), to detect urethane-induced mutations in the larger mammalian genome.  MDS sequencing Kras and/or Hras in different tissues of mice one week after urethane exposure and thereafter revealed that mutagenesis appears to account for the lion’s share of the substitution and position tropism of the carcinogen (4), in agreement with whole exome sequencing (2).  On the other hand, the Kras locus (transcriptional status and amount/type of protein produced) seems to play a more prominent role in the isoform and tissue tropism of urethane (4).  We thus codified the underlying principles of each level of the RAS mutation tropism of urethane, which may inform the mutational bias of RAS genes observed in human cancers.

1. Li S, Balmain A, Counter CM (2018) A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 18:767-77. 
2. Westcott PMK, Halliwill KD, To MD, et al. (2015) The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature. 517:489-92.
3. Jee J, Rasouly A, Shamovsky I, et al. (2016) Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing. Nature. 534:693-6.
4.  Li S, MacAlpine DM, Counter CM (2020) Capturing the primordial Kras mutation initiating urethane carcinogenesis. Nat Commun, 11:1800.

Chris Counter

Professor, Duke University

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