CIN refers to structural alterations or numerical gain or loss of chromosomes, leading to aneuploidy and the loss of heterozygosity. About 70% of CRCs may develop through the CIN pathway [2]. The gatekeeper mutation for adenoma development through the CIN pathway occurs in the APC tumor suppressor gene. Because APC plays a pivotal role in the Wnt signal transduction pathway, mutations in this gene can increase the proliferation of colorectal epithelial cells, thereby initiating adenoma development. Mutations in the K-RAS oncogene are also frequent genetic alterations in the CIN pathway. As the K-RAS protein is involved in the receptor tyrosine kinase cascade, K-RAS mutations affect cell proliferation and apoptosis. Mutations in the p53 tumor suppressor gene are involved in the progression of early adenomas to late advanced adenomas. Loss of heterozygosity of chromosome 18q also contributes to CRC development as a late event in the CIN pathway. Tumor suppressor genes located on chromosome 18q include DCC, SMAD2, and SMAD4, which are important in regulating cell proliferation and apoptosis. The development of CRC may require 10–15 years, from normal colorectal mucosa to conventional adenoma to CRC, via these multistep genetic changes in the CIN pathway.

DNA mismatch repair (MMR) systems , such as MLH1, MSH2, MSH6, and PMS2, repair errors that occur during DNA replication. If MMR dysfunction occurs, mutations in other genes cannot be repaired and multiple mutations may accumulate, accelerating the CRC carcinogenic process. Microsatellites are simple repeat nucleotide sequences of DNA that are subject to mutations and base-pair substitutions during DNA replication in the presence of MMR dysfunction. The MSI pathway refers to the carcinogenic pathway stemming from MMR dysfunction. About 10–15% of CRCs show MSI. Of these, around 20% have a germline mutation in one of four MMR genes (MLH1, MSH2, MSH6, and PMS2), a condition called the Lynch syndrome . The remaining 80% of CRCs with MSI may arise from the hypermethylation of the promoter of MLH1 [1]. The latter is an important example of epigenomic alteration and gives rise to sporadic CRCs with MSI.

CRCs that arise through hereditary MSI pathways, such as the Lynch syndrome, frequently show mutations in TGF-β and BAX, the exons of which contain microsatellites. K-RAS mutations may also occur, but p53 mutations are rare in the MSI pathway. Because MMR dysfunction increases mutation rates 100-fold, CRCs that arise through the hereditary MSI pathway may develop very rapidly, with only 3–5 years required for progression from normal mucosa to conventional adenoma to hereditary MSI CRC.

Expression of a specific gene is suppressed when CpG sequences in the promoter of that gene are methylated. The CIMP pathway of colorectal carcinogenesis involves the methylation of CpG sequences of tumor suppressor genes. The CIMP pathway is also called the serrated neoplasia pathway, because this route is the main pathway through which serrated polyps progress to CRC.

Serrated polyps can be classified as HPs, sessile serrated adenoma/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) [3]. Histologically, serrated polyps have a saw-tooth appearance, resulting from the proliferation and hyperplasia of crypt epithelium and the resultant saw-tooth infolding of the crypt. HPs can be subdivided into microvesicular type, goblet cell-rich type, and mucin-poor type HPs. SSA/Ps are thought to arise from microvesicular-type HPs and are the main precursors of CRC through the CIMP pathway. TSAs are also believed to be premalignant polyps. However, the molecular pathway from TSA to CRC is largely unknown because TSAs are very rare.

The CIMP pathway involves the hypermethylation of the promoter regions of tumor suppressor genes and/or MLH1, a specific DNA MMR gene. Hypermethylation of the MLH1 promoter can lead to MMR dysfunction followed by MSI. This pathway constitutes the carcinogenic mechanism by which SSA/Ps develop into sporadic MSI CRCs (Fig. 12.1). Tumor suppressor genes frequently silenced by the CIMP pathway include p16 and IGFBP7. BRAF oncogene mutation is another important feature in the serrated neoplasia pathway. BRAF mutations have been detected in 50–72% of microvesicular-type HPs, 70–80% of SSA/Ps, and 77% of CIMP-high CRCs, but in only 1% of conventional adenomas, supporting the hypothesis that the CIMP pathway involves the transformation of SSA/Ps to CIMP-high, BRAF-mutant CRCs [1].

Colorectal polyps have a variety of histological subtypes, with conventional adenomas, including tubular/tubulovillous/villous adenomas, SSA/Ps, and TSAs being the main types of premalignant polyp. Although some hamartomatous polyps can progress to CRCs, they are rare. Endoscopic characterization of these polyps is important for histological diagnosis, thereby determining the treatment plan.