Computational Analysis Reveals the Temporal Acquisition of Pathway Alterations during the Evolution of Cancer

SIMPLE SUMMARY: Early stage primary cancer, where the tumour has not yet spread from its site of origin, is commonly curable through surgery alone. Conversely, metastatic cancer, where the tumour has disseminated to distant sites, is almost invariably lethal and is the main cause of cancer death. Given that primary cancer is often curable, it is likely that the ability to metastasise is acquired late in the development of cancer. To investigate if specific cancer gene mutations or pathways are subject to selection at different time points during the life-history of cancer, we compared genomic data from primary and metastatic cancer and timed the acquisition of genomic alterations. The results presented here support the view that certain events are selected for late in the evolution of cancer. However, we observed no difference in the type or timing of events between primary and metastatic cancer. Taken together, our results suggest that the ability to metastasise is not acquired through evolution solely at a genomic level. ABSTRACT: Cancer metastasis is the lethal developmental step in cancer, responsible for the majority of cancer deaths. To metastasise, cancer cells must acquire the ability to disseminate systemically and to escape an activated immune response. Here, we endeavoured to investigate if metastatic dissemination reflects acquisition of genomic traits that are selected for. We acquired mutation and copy number data from 8332 tumours representing 19 cancer types acquired from The Cancer Genome Atlas and the Hartwig Medical Foundation. A total of 827,344 non-synonymous mutations across 8332 tumour samples representing 19 cancer types were timed as early or late relative to copy number alterations, and potential driver events were annotated. We found that metastatic cancers had a significantly higher proportion of clonal mutations and a general enrichment of early mutations in p53 and RTK/KRAS pathways. However, while individual pathways demonstrated a clear time-separated preference for specific events, the relative timing did not vary between primary and metastatic cancers. These results indicate that the selective pressure that drives cancer development does not change dramatically between primary and metastatic cancer on a genomic level, and is mainly focused on alterations that increase proliferation.