Tumour heterogeneity. (A) Recent molecular and genetic profiling has demonstrated significant intratumoural heterogeneity that can arise through genomic instability (leading to mutations), epigenetic events and/or microenvironmental influences. The stem cell hypothesis proposes that tumour-initiating cells are pluripotent and can thus give rise to progeny of multiple phenotypes; alternatively heterogeneity could be due to stochastic events. Temporal heterogeneity can be exacerbated by therapy (theoretically due to clonal evolution as some clones are eliminated whilst others expand). The significant molecular/genetic differences between cells in different areas within individual cancers, between primary and metastatic tumours (and potentially between cancer cells that successfully colonise different organs) have implications for the reliability of primary tumour biopsies for diagnosis, seeking biomarkers for treatment planning and responses to therapy. In addition, there is substantial inter-tumour heterogeneity. (B) shows images of two patients who presented with breast cancers of identical histological type and biochemical parameters. Four years later, one patient is clear of disease, while the other has evidence of multiple distant metastases, illustrative of between-patient heterogeneity in terms of response to therapy (clinical images kindly provided by Professor William Gallagher, with thanks to Dr Rut Klinger and Dr Donal Brennan (UCD Conway Institute).