Abstract

Recent cancer genomic studies have revealed an unexpected level of complexity and variation between and within patients. In particular, intratumour heterogeneity is an important issue with critical implications for personalised medicine. However, the lack of a quantitative model of reference with which to make sense to the tsunami of genomic data makes such variation hard to interpret. Here we present a 'Big Bang' model, whereby a tumour grows predominantly as a single expansion producing numerous intermixed sub-clones. In this model, not just public (clonal) mutations, but also the majority of detectable private (sub-clonal) mutations arise during the earliest phase of tumour growth. We validated this model by genomic profiling of 349 individual glands from 15 colorectal tumours and show that intratumour heterogeneity patterns naturally follow from the Big Bang. We also demonstrate that most detectable intratumour heterogeneity originates from private alterations acquired early during growth, and not from the later expansion of selected sub-clones. This finding exposes the profile of the primordial tumour, well before it became clinically detectable. This model has important implications in understanding the origins of intratumour heterogeneity and in designing personalised treatment strategies.