Molecular typing of colorectal cancer (CRC) is at an early stage of development with analysis of KRAS mutation status and DNA mismatch repair (MMR) deficiency representing the two major approaches currently in use for diagnosis and treatment-related purposes. RAS proteins act as molecular switches that regulate cellular processes including cell growth and survival. Activating KRAS mutations are found in 40–50% of colorectal adenomas and cancers. Detection of KRAS mutations guide the decision to use anti-EGFR antibody therapy, which is not effective in KRAS mutant cancers. MMR deficiency results in failure to repair replication-associated DNA errors, allowing persistence of mismatch mutations all over the genome, especially in regions of repetitive DNA known as microsatellites, giving rise to microsatellite instability (MSI). A high frequency of microsatellite instability (MSI-H) often with abnormal expression of MMR proteins is key to the diagnosis of Lynch Syndrome, but is also observed in ∼15% of sporadic CRC.
- microsatellite instability