Abstract A1-20: Genetic control of Kras mutation specificity in mice

The selection and specificity of mutations occurring in genes that drive cancer is a highly complex process that remains poorly understood for even the most well studied oncogenes. The specific pattern of RAS mutations across different cancers is thought to be modulated by differences in carcinogen exposure and metabolism, local DNA features and repair mechanisms, tissue-specific expression patterns and functional differences of the RAS isoforms 1 . Less is known about functional differences between the various activating mutations in RAS that may lead to selection of particular mutants in mouse or human cancers. Studies of mouse cancer models have provided evidence for strong genetic background effects on allele-specificity of Ras mutations 2 as well as on selection of particular mutations at Kras codon 61 in lung adenomas 3 . We have also recently demonstrated a major role of germline Kras status in mutation selection during initiation, where carcinogen-induced lung tumors from Kras WT mice carry mostly (94%) Q61R Kras mutations, while those from Kras heterozygous mice carry mostly (92%) Q61L mutations 4 . These data support the possibility that mutation specificity at Kras is influenced by genetic factors that may modulate, in trans , the levels or activity of Kras. In order to elucidate the genetic underpinnings of Kras mutation specificity, we characterized Kras mutations in carcinogen-induced lung tumors from a population of nearly 300 M. Musculus x M. Spretus backcrossed mice and performed genome-wide quantitative trait locus (QTL) mapping. Kras mutations occurred with complete specificity on the allele inherited from the susceptible strain, in agreement with previous observations. In addition, QTL mapping of lung cancer susceptibility was performed, and no Kras QTL was identified, in contrast to previous data obtained using other strains and breeding strategies. These approaches provide a framework for understanding the interactions between germline and somatic events that control Ras mutation specificity in cancer. References: 1. Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res 72, 2457–2467 (2012). 2. To, M. D. et al. A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat. Genet. 38, 926–30 (2006). 3. Dwyer-Nield, L. D. et al. Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains. Int J Cancer 126, 125–132 (2010). 4. Westcott, P. M. K. et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature (2014). doi:10.1038/nature13898 Citation Format: Peter MK Westcott, Minh D. To, Reyno Delrosario, Kyle D. Halliwill, Allan Balmain. Genetic control of Kras mutation specificity in mice. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-20.