Clinical research of the prediction of clinical outcome in patients with metastatic colorectal cancer treated with cetuximab
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2620436 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:By gene expression profiling (GEP) of head and neck squamous cell carcinomas (HNSCC) we were able to identify candidate biomarkers of progression free survival (PFS) in patients treated with cetuximab-based approaches (Bossi et al, Clinical Cancer Research 2016) . Here, the same samples were used for miRNA expression profiling. Integration of miRNA and gene expression data highlighted 16 miRNAs and 84 genes interconnected in a total of 245 interactions. After feature selection by smoothed t-statistic support vector machine, we identified a network 3 miRNAs and 5 genes that resulted the most relevant in predicting PFS (AUC=0.992). Overall, using a well defined clinical setting we gave the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to refinement of the biology behind and to the potential identification of a predictive model.
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Project description:Colorectal cancer (CRC) is a major cause of cancer mortality and a serious health concern worldwide. Vitamin D deficiency is associated with high CRC incidence and mortality, suggesting a protective effect of vitamin D against this neoplasia. Although the antiproliferative and prodifferentiation action of active vitamin D (1alpha,25-dihydroxyvitamin D3, 1,25(OH)2D3) on colon carcinoma cells is well documented, its potential effects on CRC stroma are unknown. Here, we show that high vitamin D receptor (VDR) expression in tumor stromal fibroblasts is associated with better overall and progression-free survival in a large cohort of CRC patients, irrespective of its expression in carcinoma cells. Consistently, 1,25(OH)2D3 inhibits the activation of patient-derived normal and cancer-associated fibroblasts, and their pro-migratory effect on carcinoma cells. Importantly, we show by global transcriptomic analyses that 1,25(OH)2D3 regulates cancer-associated fibroblast gene expression and imposes a gene signature that is associated with longer overall and disease-free survival of CRC patients. Moreover, expression of two genes from the signature, CD82 and S100A4, correlates with stromal VDR expression and clinical outcome in CRC. This study provides the first evidence that vitamin D has protective effects against CRC through the regulation of stromal fibroblasts. Characterization of 1,25(OH)2D3 action on gene expression in primary cultures of colon normal and tumor fibroblasts established from samples from colorectal cancer patients. RNA from seven paired normal and tumor fibroblast primary cultures treated with 1,25(OH)2D3 or vehicle for 48 h were analyzed.
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