Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification

Philip D Dunne,Daniel B Longley,Paul G O'Reilly,Tim Maughan,Patrick G Johnston,Mark Lawler,Darragh G Mcart,Aideen C Roddy,Susan Richman,Matthew Alderdice,Amy M B Mccorry,Simon S Mcdade,Elaine Kay

doi:10.1038/ncomms15657

Abstract

Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Here, using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis. Sample clustering alongside correlative assessment revealed variation in the ability of each signature to cluster samples according to patient-of-origin rather than region-of-origin within the multi-region dataset. Signatures focused on cancer-cell intrinsic gene expression were found to produce more clinically useful, patient-centred classifiers, as exemplified by the CRC intrinsic signature (CRIS), which robustly clustered samples by patient-of-origin rather than region-of-origin. These findings highlight the potential of cancer-cell intrinsic signatures to reliably stratify CRC patients by minimising the confounding effects of stromal-derived ITH.

Highlights

Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups
Using the random-forest (RF) methodology of generating classification scores for consensus molecular subtype (CMS) subtypes we observe an increased relative CMS4 classification score in invasive front (IF) samples when compared to their patient-matched central tumour (CT) samples for almost 90% of patients, which, in line with our previous work, we attribute to stromal-derived ITH (Fig. 1a)
This increase is not observed in classification scores for CMS1 or CMS3, while the epithelial-rich CMS2 displayed a general decrease in classification score in IF samples compared to the CT (Fig. 1a)

Summary

Introduction

Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. We have demonstrated that changes in region-specific tumour biology, associated with variation in stromal content and the underlying stromal gene expression, can lead to inaccurate CRC subtyping using CMS10 These findings suggest that even subtle changes in stromal content may undermine prospective patient stratification and disease management decisions, as the region-oforigin of the extracted tumour tissue is very often outside of the control of the molecular profiling team. We demonstrate for the first time that transcriptomic signatures based on cancer cell-intrinsic gene expression overcome the confounding effects of TME-related ITH and group samples by patient-of-origin rather than region-of-origin. These findings have important implications for the clinical application of transcriptomics-based patient classification approaches

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Conclusion