Back to the Colorectal Cancer Consensus Molecular Subtype Future

Abstract

Purpose of review: This review seeks to provide an informed prospective on the advances in molecular profiling and analysis of colorectal cancer (CRC). The goal is to provide a historical context and current summary on how advances in gene and protein sequencing technology along with computer capabilities led to our current bioinformatic advances in the field.

Recent findings: An explosion of knowledge has occurred regarding genetic, epigenetic, and biochemical alterations associated with the evolution of colorectal cancer. This has led to the realization that CRC is a heterogeneous disease with molecular alterations often dictating natural history, response to treatment, and outcome. The consensus molecular subtypes (CMS) classification classifies CRC into four molecular subtypes with distinct biological characteristics, which may form the basis for clinical stratification and subtype-based targeted intervention. This review summarizes new developments of a field moving "Back to the Future." CRC molecular subtyping will better identify key subtype specific therapeutic targets and responses to therapy.

Keywords: CMS; Colorectal cancer; Consensus molecular subtypes; RNAseq.

Fig. 1

A genetic model for colorectal tumorigenesis. Adapted from Fearon and Vogelstein Cell, Vol. 61, 759–767, 1990. Tumorigenesis progresses through a series of genetic alterations. These alterations include oncogenes (ras) and tumor suppressor genes (particularly those on chromosomes 5q, 17p, and 18q). Early stages involve 5q mutations or familial adenomatous polyposis coli loss. Alterations in DNA methylation may follow and then K-ras mutations. Loss of 18q or deleted in colorectal cancer (DCC) follow and then 17p loss (p53). Other alterations may precede metastasis

Fig. 2

The consensus molecular subtypes. CMS1 displays subtype clusters that involve hypermutation and microsatellite instability along with increased immune cell infiltrates consisting of Th1 lymphocyte, cytotoxic T cell, NK cell infiltration, and upregulated immune checkpoints such as PD-1. CMS2 clustering involves the upregulation of canonical pathways including WNT and MYC downstream targets. CMS3 clustering is defined by dysregulation of metabolic pathways including carbohydrate and fatty acid oxidation and the loss of T_H17 cells. CMS4 clustering is referred to as a mesenchymal subtype that involves the upregulation of EMT pathways. CMS4 clustering also shows elevated TGF-β signaling, matrix remodeling, angiogenesis, complement activation as well as integrin-β3 upregulation, stromal infiltration, immune upregulation, and platelet signatures