Cancer heterogeneity and "the struggle for existence": diagnostic and analytical challenges

The notions of inter- and intra-tumour heterogeneity (ITH) have been recognised for many years but recent advances in sequencing technology are allowing the true extent of both forms of heterogeneity to be revealed in detail for the first time. In this review we examine the current evidence for ITH, the possibility of cancers following a branched rather than linear evolutionary path and the potential implications both of these may have for the mechanisms of drug resistance acquisition. We also note that although clearly present in many cases, heterogeneity and branched evolution are not universal, with cases of tumour homogeneity and linear evolution still detected relatively frequently. The complexity induced by cases of ITH presents a considerable challenge for bioinformatics analyses and we illustrate this by describing the specific case of point mutation detection and a number of approaches which have been taken to combat these issues. Equally, the sequencing procedures which generate these data are rendered much more difficult in the face of ITH and we present a discussion of these problems in addition to describing some of the alternate paradigms being considered to overcome them.