Abstract 1923: Distinct evolutionary and mutational patterns in oncogenes and tumor suppressor genes

Abstract

Abstract Oncogenes and tumor suppressor genes play different roles in carcinogenesis and tumor progression. However, very little attention has been paid to compare their mutational and evolutionary patterns. As such, these two groups of genes are often mingled together in computational modeling and analysis. To bridge this gap, we examined the evolutionary profiles of 150 oncogenes and 102 tumor suppressor genes and their somatic mutations recorded in the COSMIC database. We found that these two groups of genes display distinct evolutionary and mutational patterns. In general, oncogenes are more conserved than tumor suppressor genes, as revealed by multiple-species comparisons. The stronger purifying selection on oncogenes is also reflected at positions harboring somatic missense mutations. Thus, somatic mutations disrupting oncogenes tend to have higher functional impact than those disrupting tumor suppressor genes. However, the mutational landscape of oncogenes is often dominated by one or very few hotspots, while multiple hotspots and frequent sporadic mutations are found in tumor suppressor genes. Furthermore, CpG hypermutations contribute to 58% of highly recurrent mutations in tumor suppressor genes, but only 4% to those in oncogenes. These patterns indicate that most random somatic mutations in oncogenes are also under stronger purifying selection as compared to those in tumor suppressor genes. However, once an advantageous mutation in an oncogene arises, it tends to increase the fitness significantly such that a hard sweep pursues, which eventually reduces the mutational diversity of the tumor. On the contrary, the relatively mild selection on tumor suppressor genes allows more neutral mutations to accumulate. When eventually the deactivation of both copies of a tumor suppressor gene triggers positive selection, the mutational diversity of the tumor has increased significantly. These distinct evolutionary and mutational patterns warrant independent modeling of oncogenes and tumor suppressor genes in studies that incorporate these features in the analysis, such as prediction of driver mutations or inference of evolutionary paths for cancers. Citation Format: Li Liu, Yung Chang, Jieping Ye, Sudhir Kumar. Distinct evolutionary and mutational patterns in oncogenes and tumor suppressor genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1923. doi:10.1158/1538-7445.AM2015-1923