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

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.

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

“…Data presented here, in addition to these referenced studies (12,(18)(19)(20), highlight that expression of a small number of genes in fibroblasts associated with the tumor, in combination with the overall fibroblast content, is sufficient to identify poor prognostic patients in stage II colorectal cancer. It is unsurprising therefore that the prognostic value of the CMS4 subtype, and indeed other current transcriptional-based prognostic classifiers, is highly dependent on stromal-derived gene signatures and that our 30-gene Stromal Classifier also identifies a group of patients with a worse prognosis.…”

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

“…In addition to the quantity of tumor stroma, its composition may be an important determinant of cancer behavior. For example, the presence of cancer-associated fibroblasts (CAFs) effectively predicts tumor recurrence in CRC patients [102]. Recently, an immune-histochemical score based on the expression of two proteins specific for CAFs has additionally been able to predict the response to neoadjuvant treatment in rectal cancer [103].…”

Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress

“…Furthermore, CAFs secrete ECM and proteases including cathepsins, plasminogen activators, and matrix metalloproteases, consequently induce EMT and increase invasive growth of CRC cells (Tommelein et al, ). It has been shown that the 5‐gene signature derived from CAF (CCL11, AMIGO2, ULBP2, SLC7A2, and PDLIM3) predicts risk of recurrence in stage II patients precisely compared to conventional clinicopathological criteria alone (Berdiel‐Acer et al, ). Interestingly, CAFs amplify the membrane‐bound serine protease, fibroblast activation protein (FAP) which is not detectable in normal fibroblasts.…”

“…patients precisely compared to conventional clinicopathological criteria alone(Berdiel-Acer et al, 2014). Interestingly, CAFs amplify the membrane-bound serine protease, fibroblast activation protein (FAP) which is not detectable in normal fibroblasts.…”