Molecular pathological classification of colorectal cancer.
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.
Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK.
Mike F
MF
Müller
Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK.|Bedford Hospital NHS Trust, Viapath Cellular Pathology, Kempston Road, Bedford, MK42 9DJ, UK.
Ashraf E K
AE
Ibrahim
Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK. M.Arends@ed.ac.uk.
Mark J
MJ
Arends
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D057089:Pathology, Molecular; D018631:ras Proteins / Q000378:metabolism
D018631:ras Proteins
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