Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer.
Colorectal cancer (CRC) is the second leading cause of cancer-related death. Despite the progress that has been made towards the identification of the molecular mechanisms involved in CRC, currently there are many unclear points. The current opinion is that microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) seem to play a significant role. MSI is related to point mutations in defect mismatch repair system of DNA. There are two well-established MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L or MSS). CIN refers to a different cellular event which originates from the presence of an abnormal chromosome complement or number. CIMP is the third most commonly involved event, and is defined by widespread methylation of CpG islands of suppressor promoters, with two phenotypes: CIMP-high and CIMP-low which interact with MSI or CIN status V-raf murine sarcoma viral oncogene homolog B (BRAF) is a serine-threonine protein kinase that acts as a downstream effector of the Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway. Various studies have revealed that BRAF V600E mutations appear to be a valid indicator of poor prognosis. KRAS is a proto- oncogene which encodes a GTP-ase involved in cellular response to extracellular stimuli. Its prognostic value is still controversial. However, wild-type KRAS is associated with better response to Endothelial Growth Factor Receptor inhibitors combined with standard chemotherapy. Loss of Heterozygosity, especially involving 18q, is a well-known potential mechanism for tumorigenesis that has been studied in CRC. Vascular endothelial growth factor is a pro-angiogenic factor linked with the aggressiveness of CRC. Emerging data show that cycloxygenase 2 overexpression is significantly associated with worse outcomes in CRC. Recent studies highlight mi-croRNAs as promising prognostic biomarkers. More specifically, the down-regulation of miR-451, miR-625, miR-29c, miR-126, miR-129 and miR133 is purported to be a poor prognostic factor, while miR-224 was overexpressed in CRC.
Department of Colorectal Surgery, Hambleden Wing, 3rd Floor, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, U.K. msideris@nhs.net.
Michail
M
Sideris
Savvas
S
Papagrigoriadis
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D011379:Prognosis; D000090063:Proto-Oncogene Mas
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas
BRAF; CIMP; CIN; CRC biomarkers; KRAS; MSI; miRNA; review