title: Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer.
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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Dunne
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: O'Reilly
authors.affiliation: Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Helen G
authors.initials: HG
authors.lastname: Coleman
authors.affiliation: Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Ronan T
authors.initials: RT
authors.lastname: Gray
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
authors.affiliation: Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Darragh G
authors.initials: DG
authors.lastname: McArt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018925:Chemokines / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000276:immunology; D032921:Consensus; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D062792:MARVEL Domain-Containing Proteins / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C432676:CKLF protein, human; D018925:Chemokines; D062792:MARVEL Domain-Containing Proteins
keywords: chemokine-like factor; colorectal cancer; gene expression profiling; molecular stratification; relapse risk