**2.1 Chromosomal instability**

The most frequent model of phenotype group in colorectal cancer are allelic losses in the short arm of chromosome 17 and 8 and in the long arm of chromosomes 5, 18 and 22, being approximately 80% of the sporadic form and are related to mutations in tumor suppressor genes of TP53 genes, APC, SMAD2, and SMAD4.

The first major accepted model for cancer development in colon was described by Fearon and Vogelstein in 1990. The majority of the sporadic CCR tumors originates from premalignant precursor lesions known as polyps, which over time progress to clinically relevant tumors. In this model, the sequence of events leading from the adenoma (polyps) to carcinoma was based on mutation on APC and TP53 genes [13, 14].

The proto-oncogene K-ras (Kirsten-ras) tumor suppressor genes, APC protein (adenomatous polyposis coli), DCC protein (deleted in colorectal cancer) and TP53; and DNA repair or mismatch repair genes (MSH2, MLH1, PMS1, PMS2 and MSH6) are fundamental in development of CCR. Repetitive nucleotide sequences form approximately 25–40% of the DNA molecule being observed several times across the genome as dispersed replicates and tandem or satellite replicates [15]. These replicates can be classified according to the extension of the repetitive sequence in: satellite, minisatellite and microsatellite, depending on the number of nucleotides [16].

Most of the cases of CCR originate from polyps, but it was evidenced that about 45% of the tumors located in the proximal colon originated from epithelium without preexisting polyps, being considered new cancer [17]. In this model of carcinogenesis, which affects 10–15% of cases of sporadic CCR, instead of chromosomal instability there would be genomic instability due to mutations of DNA repair proteins, a phenomenon known as microsatellite instability (IMS) [18]. This pathway of colorectal carcinogenesis due to chromosomal instability is more frequently observed in tumors in the proximal colon, presenting characteristic histological features, being diploid, exophytic growth, worse histological grade, greater tendency to mucus production and lower mutation index in the TP53 gene, and paradoxically, they are associated with a better prognosis [18, 19].
