The temporal evolution of cancer hallmarks

Cancer hallmarks describe key physiological characteristics that distinguish cancers from normal tissues. The temporal order in which these hallmarks appear during cancer pathogenesis is of interest from both evolutionary and clinical perspectives but has not been investigated before. Here, we order hallmarks based on the allele frequency and selective advantage of mutations in cancer hallmark genes across > 10K untreated primary tumors and > 8K healthy tissues. Using this novel approach, we identified a common evolutionary trajectory for 27 of 32 cancer types with genomic instability appearing first and immune evasion appearing last. We demonstrated widespread positive selection in cancer and strong negative selection in normal tissues for all hallmarks. Notable exceptions to the hallmark ordering in tumors were melanomas (uveal and skin) suggesting that strong environmental factors could disrupt common evolutionary paths. Clustering of hallmark trajectories across patients revealed 2 clusters defined by early or late genomic instability, with differential prognosis. We finally validated our results in about 3K primary tumors from the PCAWG consortium. Our study is the first to identify the temporal order of cancer hallmarks during tumorigenesis and demonstrate a prognostic value that could be exploited for early detection and risk stratification across multiple cancer types.