Project description:Purpose: A 128-gene signature has been proposed to predict poor outcomes in patients with stage II and III colorectal cancer. In the present study we aimed to validate this previously published 128-gene signature on external and independent data from patients with stage II and III colon cancer.
Project description:High-throughput proteomics profiling-derived signature associated with chemotherapy response and survival for stage II/III colorectal cancer
Project description:Defining molecular features that can predict the response to chemotherapy for stage II-III colorectal cancer (CRC) patients remains challenging in cancer research. Most available clinical samples are Formalin-Fixed and Paraffin-Embedded (FFPE). Affymetrix GeneChip® Human Transcriptome Array 2.0 (HTA) is one platform marketed for high-throughput gene expression profiling for FFPE tissue samples. In this study, we analyzed the whole transcriptom gene expression of 156 CRC patient samples measured by this platform to identify biomarkers predicting the response to chemotherapy for stage II-III CRC patients.
Project description:Colorectal cancer (CRC) has one of the highest worldwide incidences and mortality rates. Compared to surgery alone, adjuvant 5-Fluorouracil (5FU)-based chemotherapy improves 5-year overall survival (OS) in only 3-4% of stage II and 15-20% of stage III patients in unselected populations. Significant advances have been made in the molecular stratification of CRC, with the emerging Consensus Molecular Subtype (CMS) and Colorectal Cancer Intrinsic Signature (CRIS) transcriptomics-based classification systems; however, the therapeutic impact of molecular stratification has so far been limited. In an effort to identify subgroups of patients benefitting from chemotherapy, we assessed which CMS and CRIS subgroups of stage II and III CRC benefitted from adjuvant 5FU-based chemotherapy using in-house and published datasets.
Project description:Relapse and metastatic progression is a frequent event in colorectal cancer patients detected at early stages. The risk of recurrence requires the development of new biomarkers to correctly predict biological behavior of early stage II and stage III patients and their response to adjuvant chemotherapy. Here, we combined the proteomic quantification of secreted proteins involved in metastasis with a transcriptional analysis to develop a risk score algorithm based on the expression of six genes (SEC6). The SEC6 signature was predictive of survival and recurrence for stage II and III patients in four different datasets including a total of 1534 patients and was also associated with deficient mismatch repair, CpG-island methylator positive status and BRAF mutation. SEC6 was also predictive of beneficial or detrimental effects from 5-Fluorouracil-containing regimes and the improved response to more aggressive chemotherapies based on FOLFOX and FOLFIRI. In summary, the SEC6 risk-score algorithm may constitute a new tool for decision-making in colorectal cancer management.
Project description:Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.
Project description:We obtained fibroblast cultures from fresh surgical specimen ressected from patients with primary colorectal carcinoma: normal colonic fibroblasts (NCF=9) from the normal colonic mucosa at least 5-10cm from the surgical margin, carcinoma-associated fibroblasts from the primary tumor (CAF-PT=14) and carcinoma-associated fibroblasts (CAF-LM=11) from fresh surgical specimens of liver metastases. We identified 277 probes, in common between the three types of fibroblasts, whose expression level is sequentially deregulated according to cancer progression (NCF→CAF-PT→CAF-LM; fold change Log2 normalized expression>1.5 in each step). Prediction Analysis of Microarrays was applied to obtain a 25-gene signature that better characterizes each fibroblast class. The signature is able to classify patients carrying primary tumors according to prognosis. This fact was exploited to obtain a 19-gene signature (from the 277 deregulated probes) predicting recurrence with high accuracy in stage II/III colorectal cancer patients. Signature validation has been carried out in two independent datasets and in a meta-cohort of 336 stage II/III patients. Since the 25-gene signature was obtained regardless of gene expression data of tumor specimens or patient’s clinical data, the prognostic power of this signature provides strong evidence of the link between the tumor stroma and cancer progression. Furthermore, the 19-gene signature was able to identify low-risk patients with very high accuracy, especially relevant for those high-risk stage-II patients. We hybridised fibroblast RNA in Affymetrix GeneChip 1.0 st arrays
Project description:This series is part of a larger series (GSE24549) of colorectal cancer tissue samples analyzed for global gene expression. The expression measures were used to develope a gene signature for prediction of prognosis in stage II and III colorectal cancer.