**4. The serrated neoplastic pathway**

The pathogenesis of CRC is a heterogeneous and complex process. The classic model of adenoma-carcinoma sequence was initially described by Vogelstein and accounts for approximately 80% of sporadic CRC [19]. Mutation of the tumour suppressor gene, APC, occurs early in the process and additional mutations and chromosomal instability leads to neoplastic progression [20].

The serrated neoplastic pathway is an alternative model of CRC pathogenesis with distinct morphologic and molecular characteristics. It is estimated about 20% of CRC develop via this pathway. These lesions develop from aberrant crypt foci and hyperplastic polyps (HP) into traditional serrated adenoma (TSA) and sessile serrated adenoma (SSA), with malignant potential. BRAF mutation occurs early in the pathway, shown to be present in HP, hyperplastic adenomas and SSA [21].

SSA are also characterised by the CpG island methylator phenotype (CIMP) [22]. A cytosine nucleotide followed by a guanine nucleotide (CpG dinucleotide) can be found in dense clusters (CpG islands) in the promoter regions of approximately half of all genes [23]. Aberrant hypermethylation of these CpG islands can lead to silencing of tumour suppressor genes that, in turn, lead to carcinogenesis. CIMP can be described as high, low or negative. Hypermethylation of the mismatch repair gene *MLH1* results in microsatellite instability (MSI) in sporadic CRC [24].

MSI is implicated in 15% of sporadic CRC and >95% of Hereditary Non Polyposis Colorectal Cancer (HNPCC), also known as Lynch syndrome. It is caused by deficiency of the DNA mismatch repair (MMR) system, composed of multiple interacting proteins including MSH2, MLH1. The majority of sporadic MSI high CRC is due to the hypermethylation of the mismatch repair gene *MLH1* [25]. Sporadic MSI high CRC is also associated with BRAF mutation. BRAF mutations have been observed in 30–50% of MSI high CRC compared with 10% in microsatellite stable tumours [26, 27]. Germline mutations in 1 of 4 mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) account for the majority of cases of HNPCC. BRAF mutations rarely occur in patients with germline mutations in MMR genes [28].
