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

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.

Exploring the impact of body mass index on tumor biology and cancer development

“…This indicates that on a genomic level, there is no difference between the molecular drivers of cancer between small and large tumors. These results thus follow the pattern of previous research, where we and others have found that there is no signi cant difference between the cancer driver landscape between primary and metastatic tumors 27,48 .…”

“…For the enrichment analysis we looked at cancer driver mutations. Mutations were annotated as driver events using Annovar 26 as previously described in Ahrenfeldt et al 27 . Brie y we used PolyPhen 28 and SIFT 29 to predict if mutations were deleterious (tumor suppressor genes) or pathogenic (oncogenes).…”

Therapy drives genomic evolution in metastatic cancer

“…While this gene set is of limited scope relative to the full size of the human genome, these genes harbored more than 50% of the cancer driver mutations found in 2520 metastatic tumors analyzed by the HMF study [ 8 ], making it valid for the analysis of cancer driver mutations across the largest cohort of samples analyzed to date. Consistent with previous work suggesting clonal bottlenecking is common during metastatic dissemination [ 9 – 11 , 14 ], we observed an increase in tumor mutation burden and chromosomal instability in metastatic tumors ( Figure 1A ). However, individual driver mutations showed limited variation between primary and metastatic disease.…”

“…When we consider our own recent work [ 12 , 14 ] and that of others [ 1 , 8 – 11 ], there is limited evidence for the existence of specific gatekeeper mutations. Rather, the strong correlation observed between genomic events in primary and metastatic tumors indicate that in the absence of treatment, the evolutionary pressures are similar and from a genomic standpoint mostly focused on acquisition of aggressive cancer traits through inactivation of tumor suppressor genes such as TP53, and activation of proliferative genes such as MYC.…”