GENE-52. ANALYSIS OF RECURRENT MUTATIONS WITHIN CANCERS REVEALS PATTERNS OF DIRECTIONAL EVOLUTION IN BRAIN TUMORS

Abstract

Abstract INTRODUCTION Intratumor genetic heterogeneity is commonly caused by a stochastic evolution, but can also show remarkable selectivity resulting in directional evolution. We hypothesized that directional evolution is driven by its genetic onset-stage. This process could enforce already existing traits resulting in an enhancement of linear pathways rather than the complementary/parallel evolution. METHODS We generated a prediction model for directional evolution based on its genetic onset-stage. We performed a comprehensive analysis of 16 different tumor types of ~10,000 patients of whole-exome sequencing and copy number variation, obtained from The Cancer Genome Atlas. RESULTS We found in 5% of the patients that directional evolution occurs on a fixed genetic onset stage. There is a strong relationship between the frequencies of directional evolution and the frequencies of commonly co-occurring mutations in the onset stage. These co-occurring mutations are frequently observed in the same chromosomal region and occasionally in the same pathway. Brain tumors show a frequent directional evolution towards EGFR mutations and to a lesser extent PIK3CA mutations. CONCLUSION Given these strong correlations and since directional evolution is apparently a highly selective process, our prediction model could predict more effective therapies by choosing therapies targeting both the mutated gene that is affected by directional evolution as well as the commonly occurring co-mutated genes.