Pathogenesis of Colorectal Cancer

Our understanding of the genetic and molecular changes leading to the development of colorectal cancer (CRC) continues to evolve. A complex system of checks and balances maintains normal colorectal mucosa homeostasis and integrity during cell division and replication. Alterations in these mechanisms can lead to malignant change (Figure 2.1). In general, colorectal cancer results from a multistep process that entails the accumulation of genetic and epigenetic changes over time. Mutations in oncogenes may result in over-expression of a gene or pathway, leading to constitutive cellular signaling or proliferation. Conversely, mutations or loss of tumor suppressor genes may remove an inhibitory signal that produces uncontrolled cell growth. Furthermore, mutations in caretaker genes may lead to oncogenesis by losing the ability to induce apoptosis or repair damaged DNA. The underlying genetic and epigenetic changes leading to colorectal cancer influence the disease course including clinical phenotype, prognosis, and response to therapy. Clinical management and research must be executed with the knowledge that colorectal cancer is not a single entity but rather a heterogeneous disease, different in each person.[1]

Figure 2.1

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

Chromosomal instability is the most common form of genomic instability in colorectal cancer, accounting for about 75% of all colorectal cancers.[2] Chromosomal instability refers to an alteration in the chromosome copy number or structure. Physical loss of a chromosome segment may delete entire genes and produce loss of heterozygosity for those genes. That is, when one allele is lost, only one functional copy of the gene exists and there is no longer redundancy for that gene. Loss of the second allele then results in complete loss of that gene function (Figure 2.2). Adenomatous polyposis coli (APC) and p53 are examples of tumor suppressor genes, whose loss via this mechanism results in chromosomal unstable colorectal cancer. The traditional adenoma-to-carcinoma sequence as described by Vogelstein and Fearon is characterized by the accumulation of genetic changes over time and the prototypical chromosomal instability colorectal cancer.[3] Clinically, colorectal cancers arising via chromosomal instability tend to arise in the left colon, have male predominance, and develop later in life. Genetically, key genes mutated in this pathway include adenomatous polyposis coli (APC), KRAS, and p53.[2]

Figure 2.2

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.[2] Mutations in the APC gene lead to transcription of no protein or a protein without normal function. Decreased quantity or function of APC protein allows for intracellular accumulation of β-catenin and thus its increased translocation into the nucleus where it serves as a transcription factor responsible for proteins involved in cell signaling, proliferation, and cell-to-cell adhesion.

KRAS is an oncogene involved in the mitogen-activated protein kinase (MAPK) pathway whose upstream signaling receptor is the epidermal growth factor receptor (EGFR).[2] This pathway drives nuclear transcription of cellular proliferation. Oncogenic mutations turn on the KRAS signal and drive uncontrolled cell growth, regardless of upstream signaling. Mutant KRAS proteins provide constitutive MAPK signaling, and upstream blockage of EGFR is ineffective in blocking MAPK. KRAS mutations are present in nearly 40% of colorectal cancer.[4] In practical terms, the tumor should be tested for the KRAS mutation if the patient is being considered for anti-EGFR therapy.