Abstract
The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026.
Highlights
Current classifications of sporadic colorectal cancer take into consideration stage, histological type and grade [1]
We recently reported Colorectal cancer (CRC) expressing a BRAF mutated signature [6], which strongly overlaps with the methylation-based group of Hinoue [11], and a microsatellite instability (MSI)-like gene expression group that captures the hypermutant tumours of The cancer genome atlas (TCGA) [13], indicating the potential for identification of robust biological subgroups
The assignment of genes to gene modules and gene module clusters is listed in Table S1; meta-gene expression profiles for the discovery set are shown in Figure 1A; and between meta-gene correlations in Figure S1C
Summary
Current classifications of sporadic colorectal cancer take into consideration stage, histological type and grade [1]. Colorectal cancer (CRC) is a highly heterogeneous disease, with clinicopathologically similar tumours differing strikingly in treatment response and patient survival. These differences are only partly explained by current concepts regarding the molecular events leading to CRC. Microsatellite instability (MSI) emerged as an important classifier with significant prognostic impact and potential for patient stratification for therapy [2,3]. As well as the mutation status of BRAF or KRAS genes (predictive for anti-EGFR [4]), are in use for treatment decisions and patient stratification. Patient groups defined by these molecular markers still differ remarkably in behaviour and therapy response [5,6]. Several approaches to further subtype CRC have been proposed, based on combinations
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