| Genetic factors|
|APC||The Adenomatous Polyposis Coli (APC) gene, located on chromosome 5, is a tumor suppressor, which is mutated in most of sporadic cases of colon adenocarcinomas. APC mutation leads to an increased amount of β-catenin and to the activation of the Wnt signaling pathway that is involved in cellular activation [20–22].|
|Chromosomal instability||Chromosomal instability is a common factor that intervenes in the adenoma-carcinoma sequence. It causes the inactivation of wild-type allele of tumor suppressor genes, such as SMAD4, APC, and p53, the loss of heterozygosity, and the alteration in chromosome number, like aneuploidy [22–24].|
|BRAF and RAS||RAS and RAF are two oncogenes which activate the mitogen-activated protein kinase (MAPK) pathway. KRAS has a GTPase activity that activates RAF proteins; BRAF’s serine-threonine kinase activity initiates the MAPK signaling cascade, with the activation of several transcription factors. The result is cell survival, proliferation, and metastasis .|
Already small polyps present BRAF mutation, whereas in serrated adenomas, hyperplastic polyps and proximal colon cancer RAS is more often mutated [26, 27].
|DCC||Deleted in Colorectal Cancer (DCC) is a tumor suppressor gene sited on the long arm of chromosome 18 (18q21.3). It is a transmembrane protein that stops cell growth in absence of Netrin and its ligand. Its mutation prevents the bond with Netrin-1 and results in abnormal cell survival. Loss of heterozygosity (LOH) of chromosome 18q is seen in more than 70% of advanced CRC [23, 28, 29].|
|Family history||FAP, Familiar Adenomatous Polyposis, is an autosomal dominant disease caused by germ line mutation of APC gene. Patients affected by FAP develop thousands of polyps in gastrointestinal system, especially in the colon, starting from the second decade of life; if not treated they will develop a CRC in early adulthood [30–35].|
|Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch Syndrome is the most common hereditary form of CRC (2–4% of all CRC) [30, 36]. A characteristic trait of NHPCC is Microsatellite Instability (MIS) due to the inherited mutation of the Mismatch Repair Genes (MMR) that control the length of microsatellites, short nucleotides’ sequences repeated in DNA [37, 38].|