Molecular classification of colorectal cancer

It would undoubtedly be more convenient for cancer researchers if CRC could be viewed as a homogeneous disorder, because an individual CRC or cell line could then be considered representive of all CRC. At one level this may still be true, insofar as the acquisition of the full malignant phenotype probably depends upon the combined disruption of all the major signalling pathways. Indeed, while it has been argued above that familial and sporadic MSI-H CRC evolves through different pathways, there is very considerable overlap in the altered gene expression signatures of these two types of CRC, as shown by microchip array-based analysis.107 However, this does not refute the concept that the pathways differ at a fundamental level. Rather, it highlights major limitations of present-day biotechnology insofar as it is incapable of either explaining the evolutionary history of a malignancy or resolving subtle differences in levels of gene expression existing at the key control points of signalling pathways. Based primarily on: (i) the underlying types of genetic instability, and (ii) the presence of DNA methylation, the following five molecular subtypes of CRC (with approximate frequencies) are suggested:

1. CIMP-high, methylation of MLH1, BRAF mutation, chromosomally stable, MSI-H, origin in serrated polyps,known generally as sporadic MSI-H (12%).
2. CIMP-high, partial methylation of MLH1, BRAF mutation, chromosomally stable, MSS or MSI-L, originin serrated polyps (8%).
3. 3 CIMP-low, KRAS mutation, MGMT methylation, chromosomal instability, MSS or MSI-L, origin in adenomas or serrated polyps (20%).
4. CIMP-negative, chromosomal instability, mainly MSS, origin in adenomas (may be sporadic, FAP associated or MUTYH (formerly MYH) polyposis associated108) (57%).
5. Lynch syndrome, CIMP-negative, BRAF mutation negative, chromosomally stable, MSI-H, origin in adenomas (3%) (described also as familial MSI-H CRC in this review).

Sporadic MSI-H CRCs are deliberately termed as group 1 because they are the most obviously homogeneous group with respect to their clinical, morphological and molecular features. However, group 5 CRCs share features with group 1 CRCs and these groups may be conceived as completing a circle rather than representing the ends of a spectrum (Figure 1). Overlaps between the groups are not excluded. For example, KRAS rather than BRAF mutation may occasionally occur in association with CIMP-high.