Molecular classification and correlates in colorectal cancer

Abstract

Molecular classification of colorectal cancer is evolving. As our understanding of colorectal carcinogenesis improves, we are incorporating new knowledge into the classification system. In particular, global genomic status [microsatellite instability (MSI) status and chromosomal instability (CIN) status] and epigenomic status [CpG island methylator phenotype (CIMP) status] play a significant role in determining clinical, pathological and biological characteristics of colorectal cancer. In this review, we discuss molecular classification and molecular correlates based on MSI status and CIMP status in colorectal cancer. Studying molecular correlates is important in cancer research because it can 1) provide clues to pathogenesis, 2) propose or support the existence of a new molecular subtype, 3) alert investigators to be aware of potential confounding factors in association studies, and 4) suggest surrogate markers in clinical or research settings.

Figure 1

CIMP classification in colorectal cancer and associations with clinical and molecular features.

Figure 2

The six groups of colorectal cancer according to MSI and CIMP status.

Figure 3

The four major subtypes of colorectal cancer according to MSI and CIMP status.

Figure 4

A: Frequency of BRAF mutation in the four major subtypes of colorectal cancer (data in Ref.⁸⁶). B: Frequency of p53 positivity (by immunohistochemistry) in the four major subtypes of colorectal cancer (data in Ref.⁷⁶). C: Frequencies of CIMP-high and MSI-H in colorectal cancer according to combined p53 and p21 (CDKN1A) status (data in Ref.⁷⁵).

Figure 5

A: Molecular correlates in colorectal cancer. Note that MSI and CIMP (in the blue circle) are present centrally in this figure of the molecular correlates, implying their influence on various molecular alterations (indicated as “p53,” “p21,” etc) and a phenotype in colorectal cancer. B: Molecular correlates in colorectal cancer in the past (particularly without our current knowledge on CIMP and BRAF mutation). This figure is much simpler than A.