PROJECT SUMMARY/ABSTRACT
The RAS family comprised of KRAS, NRAS, and HRAS are the most commonly mutated oncogenes in human
cancer. Despite there being over 50 possible oncogenic RAS mutations, each cancer type has 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 reflect fundamental biology underlying the process of
tumor initiation. Elucidating the mechanisms giving rise to RAS mutation patterns would therefore address
a foundational question in cancer biology- how cancer originates. Given this, the most informative approach to
interrogate these patterns is to study RAS mutations when they 1) first occur in 2) normal cells in an 3) in vivo
setting. Trying to backtrack to catch that one random mutagenic event in one gene from one cell that initiates
cancer decades before manifesting as a disease is challenging in humans. There are, however, two murine
model systems that allow an initiating RAS mutation to be precisely defined, and hence are amenable to studying
RAS mutation patterns. One, carcinogenesis, which is particularly well suited to interrogate how the mutagenic
process gives rise to RAS mutation patterns. Two, genetic activation of mutant alleles in a spatially and
temporally restricted fashion, which is ideal to study the response of defined Ras mutations in normal cells. We
thus propose to capitalize on the individual strengths of these two different models to elucidate the mechanisms
by which RAS mutation patterns are laid down in normal cells at the very onset of tumorigenesis in vivo.
Specifically, in aim 1 we will determine how tumors arise by a specific Ras mutation by monitoring mutagenesis
immediately after carcinogen exposure and thereafter in genetic backgrounds that alter RAS mutation patterns.
In aim 2 we will determine the signaling and cellular responses of different normal cells upon genetic induction
of different oncogenic Ras mutants. Completion of this proposal will thus elucidate the principles underlying the
selection for specific RAS mutations in human cancers, and more broadly, how cancers originate, which has
clinical implications for early detection and prevention.