Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, <20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor significantly contributes to tumor regression. was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with downregulation in human cancers. Induced expression significantly reduced tumor cell proliferation The RAS pathway is frequently altered in human cancers, and activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.