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.
Highlights
Colorectal cancer (CRC) is one of the most common cancer types in men and women worldwide, with more than one million new cases recorded annually [1]
The expression of classifier genes is mainly fibroblast-specific (Supplementary Figure 1A). To demonstrate that these five genes have prognostic value if the stroma is present in a given sample, we checked our signature in two independent datasets of LCM (Laser Capture Microscope) epithelial cell-enriched samples
We excluded a possible contribution of cells to the epithelial to mesenchymal transition (EMT) process that would account for the expression of classifier genes (Supplementary Figure 1F-G)
Summary
Colorectal cancer (CRC) is one of the most common cancer types in men and women worldwide, with more than one million new cases recorded annually [1]. Some patients whose clinical factors suggest that they do not have a higher risk of relapse based on clinical factors still relapse, while, on the other hand, approximately 40% of patients with Stage-III CRC enrolled in surgery-only groups did not recur in five years even without adjuvant treatment [5]. These facts demonstrate that the traditional staging system is not sufficient to identify those patients with Stage-II CRC who carry a high risk of poor outcomes, and this may lead www.impactjournals.com/oncotarget to potential under- or over-treatment in many situations. Identification of new biomarkers to improve prediction of high-risk patients with Stage-II CRC and improved individualized cancer care are needed [6]
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