Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer

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.

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…Colorectal tumours can be classified in up to six unique subtypes with diverse clinical features according to the genes they express [8][9][10][11][12] .…”

“…Expression profiles were therefore used to assign each cell line to a molecular subtype [8][9][10][11][12] by the Nearest Template Prediction (NTP) algorithm, which also estimates the classification false discovery rate (FDR) 23 . Each of the five classifiers was able to assign (FDRo0.2) the large majority of the cell lines to a subtype.…”

“…We conclude that genetic and pharmacological profiling CRC lines can successfully nominate clinically-relevant molecular determinants of response to targeted therapies. In addition to the mutation-based categories described above, CRC can be subdivided in up to six transcriptional subtypes with distinct molecular and clinical features [8][9][10][11][12] , which we found to be robustly maintained in cells grown in vitro. This observation, along with the evidence that independent cell lines derived from the same patient consistently co-cluster transcriptionally, suggests that the transcriptional profile is stable and predominantly controlled by the genome in the absence of environmental inputs.…”

“…Transcriptional profiling has been recently used to identify distinct CRC subtypes [8][9][10][11][12] . The subtypes are associated with biological and clinical features such as cell of origin, MSI, prognosis and response to treatments.…”

Original paper Can the histological type of colorectal cancer determine the carcinogenesis pathway?

“…The heterogeneity of colorectal cancer is a result of the presence of three different carcinogenesis pathways which correlate with the clinical and morphological manifestation [2,3]. We distinguish cancers with chromosomal instability (CIN), microsatellite instability (MSI) and cancers with CpG island methylator phenotype (CIMP) [4][5][6].…”