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RAS mutation tropism

Seminar speaker, Christopher Counter
Thursday, February 01, 2024
12:00 pm - 1:15 pm
Christopher Counter
Integrated Toxicology & Environmental Health Seminar Series

RAS genes are commonly mutated in human cancer, which is well established to initiate and promote tumorigenesis. Despite there being over 50 possible such 'oncogenic' mutations in these genes, each cancer type has a tropism towards a specific and often unique subset of these mutations. As RAS mutations typically occur early during tumorigenesis, if not being the initiating mutation, these mutational patterns ostensibly reflect fundamental biology underlying the process of tumor initiation. Thus, elucidating the mechanisms behind RAS mutation tropism will provide insight into one of the most foundational questions in cancer biology - how cancer originates - which has predictive and even preventative clinical implications. To determine how these patterns are established, the initiating mutagenic event has to be captured in normal cells in vivo at the moment they occur. It is challenging, if not impossible, to identify a spontaneous mutagenic event in one RAS gene in a single specific normal cell decades before manifesting as cancer in humans. However, the environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by a single specific RAS in mice. To elucidate the principles underlying this RAS mutation tropism of this carcinogen, 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.

Dr. Counter is the George Barth Geller Distinguished Professor of Pharmacology and the Associate Director of the Duke Cancer Institute. His laboratory studies the origins of human cancers.