**2. Early molecular characterisation of colorectal cancer**

It is now well established that the majority of sporadic CRC cases (85%) exhibit chromosomal instability (CIN) with changes in chromosome number and structure such as deletions, gains, translocations and amplifications. CIN is associated with inactivating mutations or losses in the APC tumour suppressor gene which occurs early in the adenoma-carcinoma sequence [3]. The remaining 15% of sporadic CRCs demonstrate microsatellite instability (MSI) through changes in the number of repeats or length of microsatellites. MSI arises through defective DNA mismatch repair (MMR) mechanisms caused by epigenetic silencing of the MLH1 gene by promotor hypermethylation [4]. Epigenomic studies have shown that MSI tumours have a high CpG island methylator phenotype (CIMP-H) which involves aberrant methylation of CpG-rich gene promoter regions. This leads to silencing of expression of critical tumour suppressor genes such as MLH1, thereby leading to the development of CRC [5]. Familial syndromes, such as Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome (HNPCC), occur through germline mutational inactivation of genes encoding MMR proteins, namely, MLH1, MSH2, PMS2 and MSH6.

Clinicopathological features and the mutational status of CRC tumours differ according to the above classification. Sporadic MSI-high (MSI-H) tumours are more likely to be right-sided (proximal), poorly differentiated, mucinous and associated with tumour-infiltrating lymphocytes (TILs) and have higher rates of BRAF mutation, whereas microsatellite-stable (MSS) tumours are more frequently left-sided (distal) and have higher rates of KRAS mutation [5].

It has been shown that MSI status has both a prognostic and a predictive role in CRC. MSI-H tumours have better stage-adjusted survival (in stages I–III) when treated with surgery alone and do not derive as much benefit from adjuvant fluorouracil-based chemotherapy as MSS tumours do [4]. In advanced disease, MSI-H tumours are associated with a worse prognosis, and this is due to their association with activating BRAF mutations [6]. It has more recently been shown that MSI status also predicts for significant response and benefit from anti-PD1 antibodies with MMR-deficient tumours exhibiting higher response rates and longer progressionfree survival (PFS) than MMR-proficient tumours [7].
