Colorectal cancer (CRC) is one of the central neoplasms worldwide, in addition to becoming a focus of attention due to its high prevalence and mortality [1]. The World Health Organization has reported that it accounted for 10.4% of all cancer diagnoses in the last five years until 2020, with an age-adjusted incidence of 28.3 cases per 100,000 inhabitants annually [2]. This disease, which originates mainly in the epithelium of the colon and rectum, has shown an alarming increase in incidence, being the second most diagnosed cancer globally [3].
The lifetime risk of CRC is similar in women and men, at 4.1% and 4.4%, respectively, although age-specific increases in incidence and mortality occur later in women than in men. The average age of diagnosis is 68 years in men and 72 years in women; however, in recent years, an increase in incidence has been observed in people younger than 50 years [4, 6].
About 80% of patients with colon cancer are sporadic; however, 20% have hereditary syndromes, which play a significant role in susceptibility to this disease. Syndromes such as Lynch syndrome or familial adenomatous polyposis follow an autosomal dominant inheritance pattern, where significant alterations occur in the genes associated with proteins responsible for repairing mismatch errors [2–4].
Certain diseases influence the site where this neoplasm appears; the behavior on the right side (cecum, ascending colon, hepatic angle and transverse colon) is related to diseases not associated with polyps, such as Lynch syndrome and diabetes mellitus, since they share signaling pathway to cause damage to target organ [5]; on the left side (splenic angle, descending colon, sigmoid colon) it is more frequent in patients with a history of polyp-related diseases [7].
CRC is a disease of significant genetic heterogeneity from different genetic and epigenetic pathways. The progression from adenoma to adenocarcinoma involves inactivation of tumor suppressor genes such as adenomatous polyposis coli (APC), tumor suppressor gene TP53 (TP53) and deleted in colorectal cancer (DCC) and mutations in Kirsten rat sarcoma oncogenes (KRAS), suppressor of mothers against decapentaplegic (SMAD) and proto-oncogene B-Raf (BRAF); which lead to genomic instability. As colorectal cancer increases in size, the adenoma portion may disappear or remain part of the tumor [8].
Kirsten rat sarcoma is a commonly mutated oncogene in CRC in 40% of all cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, leading to tumorigenesis [9].
KRAS mutations are more associated with right colon cancer than left colon cancer; they are also less likely to have a first-degree relative with CRC or to be smokers [10].
Codons 12 (G12) and 13 (G13) are the most frequent sites by up to 85%; among them, the codon 12 mutation is dominant and accounts for 65%; the remaining 5% represent mutations affected at codons 61, 146, and 154 low-grade tumors and have a less poor mismatch repair status [9].
The G12C mutation occurs at position 12 of the KRAS gene, where an amino acid cysteine (C) replaces glycine (G). This mutation produces a mutated KRAS protein with altered function, which remains constitutively active; it causes short responses to standard chemotherapy and worse overall survival than non-G12C mutations. Several KRAS G12C inhibitors have demonstrated clinical activity in recent years, although all patients eventually progressed. [11]
Identifying negative feedback through the epidermal growth factor receptor (EGFR) has led to the development of KRAS inhibitors plus an anti-EGFR combination, which enhances antitumor activity [12].
Among the genetic changes found in CRC is the p. V600E pathogenic variant of the BRAF gene, which encodes a serine/threonine kinase involved in the EGFR-MAPK signaling pathway. This variant is vital to this cancer, as it causes constitutive activation of the protein, resulting in inhibition of apoptosis and uncontrolled cell proliferation [13].
EGFR is an important therapeutic target in colorectal cancers. The essential nature of KRAS mutation testing in clinical practice to predict resistance to EGFR inhibitors during the treatment of metastatic colorectal cancer offers a promising outlook in the battle against this disease.