Oncotarget

Research Papers:

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, Paul G. O’Reilly, Helen G. Coleman, Ronan T. Gray, Daniel B. Longley, Patrick G. Johnston, Manuel Salto-Tellez, Mark Lawler and Darragh G. McArt _

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Oncotarget. 2016; 7:36632-36644. https://doi.org/10.18632/oncotarget.9126

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Abstract

Philip D. Dunne1, Paul G. O’Reilly1, Helen G. Coleman2, Ronan T. Gray2, Daniel B. Longley1, Patrick G. Johnston1, Manuel Salto-Tellez1, Mark Lawler1,*, Darragh G. McArt1,*

1Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen’s University Belfast, Belfast, UK

2Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen’s University Belfast, Belfast, UK

*These authors have contributed equally to this work

Correspondence to:

Mark Lawler, e-mail: [email protected]

Keywords: colorectal cancer, gene expression profiling, molecular stratification, relapse risk, chemokine-like factor

Received: February 15, 2016     Accepted: April 16, 2016     Published: May 2, 2016

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.


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