Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer.

Philip D Dunne,Helen G Coleman,Mark Lawler,Daniel B Longley,Darragh G Mcart,Manuel Salto-Tellez,Paul G O’Reilly,Ronan T Gray,Patrick G Johnston

doi:10.18632/oncotarget.9126

Philip D Dunne, Helen G Coleman + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.9126

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Journal: Oncotarget	Publication Date: May 2, 2016
Citations: 36	License type: cc-by

Affiliation: Queen's University Belfast

Abstract

The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four consensus molecular subtypes (CMS's) representing the underlying biology in CRC. The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis in early stage disease, but paradoxically has the worst prognosis following relapse, suggesting the presence of factors enabling neoplastic cells to circumvent this immune response. To identify the genes influencing subsequent poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse.In a cohort of early stage colon cancer (n=460), we examined, in silico, changes in gene expression within the CMS1 subtype and demonstrated for the first time the favorable prognostic value of chemokine-like factor (CKLF) gene expression in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using transcription profiles originating from cell sorted CRC tumors, we delineated the source of CKLF transcription within the colorectal tumor microenvironment to the leukocyte component of these tumors. Further to this, we confirmed that CKLF gene expression is confined to distinct immune subsets in whole blood samples and primary cell lines, highlighting CKLF as a potential immune cell-derived factor promoting tumor immune-surveillance of nascent neoplastic cells, particularly in CMS1 tumors. Building on the recently reported CRCSC data, we provide compelling evidence that leukocyte-infiltrate derived CKLF expression is a candidate biomarker of favorable prognosis, specifically in MSI-immune stage II/III disease.

Highlights

Until recently, the classification of Colorectal Cancer (CRC) has been limited to the generation of prognostic signatures based on gene expression profiles developed by supervised analysis for prognosis
We examined the prognostic value of the four identified subtypes (CMS1-4) based on 3-year relapse risk using a cohort of n=177 untreated stage II/III patient profiles with Consensus Molecular Subtypes (CMS) assignment and complete clinical follow up data (Figure 1)
There was a trend towards better prognosis in the Microsatellite Instable (MSI)-immune CMS1 compared to the CMS4 mesenchymal subgroup (3year relapse rate (RR) of 13% vs. 31%, HR=0.40, 95% CI 0.15 – 1.03) (Figure 2 and Supplementary Table 1)

Summary

Introduction

The classification of CRC has been limited to the generation of prognostic signatures based on gene expression profiles developed by supervised analysis for prognosis. The four Consensus Molecular Subtypes (CMS) identified were: CMS1: microsatellite instability (MSI) immune (frequency 14%); CMS2: canonical (37%); CMS3: metabolic (13%) and CMS4: mesenchymal (23%), providing a more granular discrimination of the underlying CRC disease biology and permitting for the first time an attempt at dissecting the clinical utility of these robust subtypes. The CMS1 subtype is characterized by a high mutation burden, due to the abundance of MSI tumors within this subtype, and a high level of immune infiltration. This subgroup has long been associated with a relatively good prognosis in early stage disease. While www.impactjournals.com/oncotarget only a relatively small proportion of patients with MSI tumors subsequently relapse, they have the worst overall prognosis [8,9,10,11]

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Conclusion