A 5-gene classifier from the carcinoma-associated fibroblast transcriptomic profile and clinical outcome in colorectal cancer

// Mireia Berdiel-Acer 1 , Antoni Berenguer 2 , Rebeca Sanz-Pamplona 2 , Daniel Cuadras 2 , Xavier Sanjuan 3 , Maria Jose Paules 3 , Cristina Santos 4 , Ramon Salazar 4 , Victor Moreno 2 , Gabriel Capella 5 , Alberto Villanueva 1 , David G. Mollevi 1 1 Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Catalonia, Spain 2 Biomarkers and Susceptibility Unit, Cancer Prevention and Monitoring Programme, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Catalonia, Spain 3 Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Catalonia, Spain 4 Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Catalonia, Spain 5 Hereditary Colorectal Cancer Programme, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Catalonia, Spain Correspondence to: Dr. David G. Mollevi, e-mail: dgmollevi@iconcologia.net Keywords: colorectal; microenvironment, carcinoma-associated fibroblast, prognosis, genetic classifier. Received: May 19, 2014      Accepted: July 14, 2014      Published: July 23, 2014 ABSTRACT Based on 108 differentially expressed genes between carcinoma-associated fibroblasts (CAFs) and paired normal colonic fibroblasts we recently reported, a 5-gene classifier for relapse prediction in Stage II/III colorectal cancer (CRC ) was developed. Its predictive value was validated in datasets GSE17538, GSE33113 and GSE14095. An additional validation was performed in a metacohort (n=317) and 142 CRC patients by means of RT-PCR. The 5-gene classifier was significantly associated with increased relapse risk and death from CRC across all validation series of Stage II/III patients used. Multivariate Cox regression analyses confirmed the independent prognostic value of the stromal classifier (HR=2.67; P=0.002). Post-test probabilities provided evidence of the suitability of the 5-gene classifier in clinical practice, identifying a subgroup of Stage-II patients who were at high risk of relapse. Moreover, the a priory worst prognosis mesenchymal subtype of tumours can be stratified according to the physiological status of their carcinoma-associated fibroblasts. In conclusion the CAFs-derived 5-gene classifier provides more accurate information about outcome than conventional clinicopathological criteria and it could be useful to take clinical decisions, especially in Stage II. Additionally, the classifier put into relevance the CAF’s intratumoral heterogeneity and might contribute to find relevant targets for depleting adequate CAFS subtypes.