**1. Introduction**

Colorectal cancer (CRC) was one of the earliest molecularly characterised solid tumours. Vogelstein et al. initially described the stepwise manner of adenoma formation to carcinoma via the accumulation of genetic and epigenetic events in the late 1980s [1]. This model provided insight into how driver alterations in the main oncogenes (KRAS, NRAS, BRAF and PI3K) and tumour suppressor genes (APC, TP53 and PTEN) were implicated in the biology of CRC [2]. The accumulation of these genetic mutations leads to carcinogenesis through deregulation of key pathways involved in cell proliferation, differentiation and apoptosis. It is now known that abnormalities of the Wnt signalling pathway are almost ubiquitous in sporadic CRC and usually arise from mutations of the APC gene [3].

Further to this, genetic and epigenetic exploration of CRC subsequently identified significant molecular heterogeneity in this disease. This was clinically evident by the differing responses to systemic therapy and varying clinical course of patients with the same stage of tumour. Biomarker discovery in CRC has arisen through the analysis of responders and nonresponders to targeted agents and the subsequent discovery of RAS mutations conferring resistance to anti-epidermal growth factor receptor (EGFR) therapies. More recently, our deeper understanding of the underlying biology of CRC has also revealed that clonal, stromal and immune characteristics of tumours are important when considering therapeutic targets. The ongoing need to accurately define molecularly distinct subgroups and identify the underlying genetic drivers as well as novel therapeutic targets within each subgroup in order to rationalise drug development continues to be of paramount importance in CRC.
