Pathogenesis of Colorectal Cancer

While a complex system of checks and balances maintains normal colorectal mucosal homeostasis and integrity during cell division and replication, alterations in these mechanisms can lead to malignant transformation (Figure 1). In general, sporadic colorectal cancer (CRC) results from a multistep process, resulting in the accumulation of genetic and epigenetic changes over time. Mutations in oncogenes may result in the overexpression of a gene or pathway, leading to constitutive cellular signaling or proliferation. Mutations or loss of tumor suppressor genes may prevent uncontrolled cell growth. Furthermore, mutations in caretaker genes may lead to oncogenesis via loss of apoptosis or DNA repair. These underlying genetic and epigenetic changes leading to CRC influence the disease course, including response to therapy.[1][2]

Figure 1. APC, KRAS, and p53 Mutations in CRC

APC, adenomatous polyposis coli

At least three major molecular pathways have been described for the development of CRC: 1) chromosomal instability; 2) microsatellite instability, and; 3) methylator phenotype. Each pathway has unique characteristics, but there is some overlap between the pathways; further, two or more pathways may co-exist in the same patient.[1]

Chromosomal instability is the most common genetic mutation in CRC, accounting for about 75% of all sporadic colorectal cancers.[3] Chromosomal instability refers to an alteration in chromosome number or structure. Physical loss of a chromosomal segment results in loss of genes, resulting in loss of heterozygosity for those genes. In other words, when one allele is lost, only one functional copy of the gene remains. Loss of the second allele then results in complete loss of that gene function (Figure 2). The traditional adenoma-to-carcinoma sequence as described by Vogelstein et al., is characterized by the accumulation of genetic changes over time.[4] Clinically, CRC arising via chromosomal instability tend to arise in the left colon, has a male predominance, and usually develops later in life. Genetically, key genes mutated in this pathway include adenomatous polyposis coli (APC), KRAS, and p53.[3]

Figure 2. Germline Mutation (Inherited disease)

APC and p53 are tumor-suppressor genes whose loss leads to CRC. The APC gene, a tumor suppressor, has been called the gatekeeper gene because it is the key initiating step to malignant transformation for many colorectal adenocarcinomas. The APC protein regulates the Wnt signaling pathway via intracellular binding of β-catenin. With mutations, there is a decrease in APC protein quantity or function which permits β-catenin to accumulate within cells.[3]

KRAS mutations are present in nearly 40% of all CRC cases.[5] KRAS is an oncogene involved in the mitogen-activated protein kinase (MAPK) pathway. Its upstream signaling receptor is the epidermal growth factor receptor (EGFR).[3][6]

The MAPK pathway drives nuclear transcription for cellular proliferation. Oncogenic mutations turn on the KRAS signal, resulting in uncontrolled cell growth independent of upstream signaling. Mutant KRAS proteins provide constitutive MAPK signaling, and upstream blockage of EGFR is ineffective in inhibiting MAPK expression in this circumstance. Therefore, the tumor should be tested for the KRAS mutation when the patient is being considered for anti-EGFR therapy.[6]