Abstract 1087: Differential oncogenicity of N-RAS mutations in melanoma.

In human cancer, N-RAS mutations resulting in constitutive, oncogenic signaling are predominately localized to codons 12, 13 or 61. Traditionally, activating RAS mutations have been considered oncogenically equivalent, yet recent studies suggest important clinical distinctions between colon cancers containing K-RAS codon 12 vs. codon 13 mutations. More than 20% of human melanomas harbor N-RAS mutations, the vast majority of which target codon 61, as opposed to N-RAS mutations of codon 12 or 13, which are common in other tumor types. To address this issue, we characterized syngeneic knock-in mouse models conditionally expressing either N-RasG12D or N-RasQ61R under the control of the endogenous locus. In primary melanocyte cultures, activation of either N-Ras allele reduced cellular proliferation even in the presence of concomitant p16INK4a deletion. Correspondingly, melanocyte-specific N-RasG12D expression combined with p16INK4a loss failed to efficiently promote melanoma formation in mice. In contrast, melanocyte-specific N-RasQ61R induction readily combined with p16INK4a loss to promote melanoma formation in vivo with short latency and high penetrance. These results provide a first murine model of melanoma featuring knock-in N-Ras mutationQ61R, and suggest that the preference for codon 61 mutations in human tumors is conserved in mice.Citation Format: Christin Burd, William R. Jeck, Kailing Fu, Kelly S. Clark, Jessie C. Xiong, George P. Souroullas, Norman E. Sharpless. Differential oncogenicity of N-RAS mutations in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1087. doi:10.1158/1538-7445.AM2013-1087

Duke Scholars

Author William Richard Jeck Pathology