CRC progression is a stepwise histological sequence over a period of generally >10 years.6 One or more of the following mechanisms give rise to CRC7:
- Chromosomal instability (CIN); associated with up to 85% of sporadic CRCs
- CIN tumors are characterized by aneuploidy and loss of heterozygosity (LOH).
Begins with acquisition of adenomatous polyposis coli (APC) mutations, followed by mutational activation of the KRAS oncogene and inactivation of TP53 tumor suppressor gene.
- CpG island methylator phenotype (CIMP); incidence varies for genes involved.
- Characterized by hypermethylation in the promoter region of tumor suppressor genes, such as MGMT and MLH1, or cell-cycle genes, resulting in their inactivation.
- Hypermethylation is often associated with BRAF mutations and microsatellite instability (MSI).
- Microsatellite instability (MSI); found in 15% of CRCs.8
- Cells with inactivating mutations in DNA mismatch repair (MMR) genes (usually from hypermethylation of the MLH 1 gene promoter) are unable to correct single-base mismatches and insertion-deletion loops that form during DNA replication. The accumulation of these errors causes the creation of microsatellite DNA fragments.
- Analysis of a panel of MSI markers stratifies patients as MSI-High (MSI-H; >30% of unstable MSI biomarkers), MSI-Low (MSI-L; <30% of unstable MSI biomarkers), or Microsatellite Stable (MSS). Those with MSI-H tumors have a more positive prognosis compared with MSI-L or MSS tumors.
The three mechanisms that promote CRC are often interdependent.7
- For example, hypermethylation of MMR genes may lead to MSI via the CIMP pathway.