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Review
. 2016 Aug;469(2):125-34.
doi: 10.1007/s00428-016-1956-3. Epub 2016 Jun 20.

Molecular pathological classification of colorectal cancer

Mike F Müller  1 , Ashraf E K Ibrahim  2   3 , Mark J Arends  4
Affiliations
Review

Molecular pathological classification of colorectal cancer

Mike F Müller et al. Virchows Arch. 2016 Aug.

Abstract

Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite instability. This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer. Two molecular pathological classification systems for CRC have recently been proposed. Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies. This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups: almost all hypermutated MSI cancers fell into the first category CMS1 (MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Although further research is required to validate these two systems, they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions, particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade.

Keywords: Cancer; Chromosomal instability; Colorectal; Consensus molecular subtypes; Defective mismatch repair; Hypermutant; Microsatellite instability; Mutation; Polymerase epsilon; Serrated pathway; Somatic copy number alterations; The Cancer Genome Atlas; Ultramutant.

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Figures

Fig. 1
Fig. 1
Molecular classification systems for colorectal cancers. On the left is a representation of The Cancer Genome Atlas integrated molecular classification of colorectal cancers into three groups: (1) ∼13 % hypermutated tumours with microsatellite instability due to defective mismatch repair, usually caused by MLH1 silencing via promoter hypermethylation, with the dMMR pathway causing a hypermutated phenotype resulting from failure to recognise and repair DNA mismatches or insertions/deletions; 80–90 % of sporadic hypermutated cancers have BRAF V600E (or similar) mutations; (2) ∼3 % ultramutated tumours with DNA Polymerase Epsilon or Delta 1 (POLE or POLD1) exonuclease domain (proofreading) mutations (EDM), with the malfunctioning enzyme introducing incorrect nucleotides during DNA replication, resulting in an ultramutated phenotype; (3) ∼84 % CIN tumours with a high frequency of DNA SCNAs, a low mutation rate (<8/Mb), microsatellite stability (MSS) and deregulation of the WNT pathway most frequently by APC mutation. On the right is a representation of the consensus molecular subtypes (CMS) expression signature-based classification with four CMS groups—CMS1 (MSI-immune, 14 %), CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Molecular attributes and expression signatures for each CMS group are indicated. (CIMP CpG Island methylator phenotype, CIN chromosomal instability, C’ complement activation signature, CMS consensus molecular subtypes, dMMR defective mismatch repair, MLH1-sil MLH1 silencing by promoter hypermethylation, MSI microsatellite instability, MSS microsatellite stability, SCNA somatic copy number alteration, POLE DNA polymerase epsilon (or D1, Delta 1)).
Fig. 2
Fig. 2
Integration of morphological and molecular features of colorectal cancer, including the serrated precursors sessile serrated adenoma/polyp and traditional serrated adenoma. a Poorly differentiated colorectal cancer (on the left) of CMS1 (MSI-immune) with prominent tumour-infiltrating lymphocytes (TILs) and underlying lymphocytes within the submucosa with adjacent muscularis mucosae and crypt bases (on the right). b Immunohistochemical stain for MLH1 showing loss of expression of MLH1 protein in the adenocarcinoma (bottom left) with positive staining for MLH1 in the overlying adenoma (top right) and adjacent lymphoid and stromal cells. c Sessile serrated adenoma/polyp showing a high-power view of the bases of dilated and serrated crypts with boot-shaped architecture and horizontal growth along the top of the muscularis mucosae, with mild nuclear enlargement but no dysplasia. d Traditional serrated adenoma showing a high-power view of an elongated dysplastic crypt with small lateral ectopic budding crypts, projecting at 90° to the main axis of the long crypt. The nuclei are elongated, displaying a pencillate pattern of low-grade dysplasia. (All photomicrographs taken at ×100 magnification)
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