Project description:Clinical Significance: Understanding the differences in colorectal cancer (CRC) aggressiveness and clinical outcomes in relation to tumor stage and different molecular subsets is at most important for designing treatment regimens. However, molecular signatures for specific phenotypic subsets that predict the aggressiveness and clinical outcomes of CRC, specifically in advanced disease stage are lacking. Therefore, for the first time, the current study has identified a set of molecular markers that are associated with aggressive Stage III CRCs that exhibited microsatellite stable and mutant p53 phenotypic features. These findings might aid in designing aggressive treatment regimens and help to provide insights into the development of novel therapeutic targets. Results: Increased incidence of p53 mutations in MSS CRCs (58%) was associated with higher CRC-specific mortality than MSS-p53 wild-type phenotypes (log-rank, P=0.025; and hazard ratio, 2.52; 95% confidence interval, 1.25-5.08). Of 49 down-regulated genes, LPAR6, PDLIM3 and PLAT and of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8, were confirmed by qNPA, qRT-PCR, and IHC platforms. Conclusions: p53 mutations are associated with poor prognosis of Stage III microsatellite stable CRCs. p53 wild type vs. mutant tumor samples
Project description:Transcription profiling by array of microsatellite stable stage III Colorectal Adenocarcinoma (MSS-CRC) with wild type or mutant p53 to study the prognostic significance of the mutation
Project description:Clinical Significance: Understanding the differences in colorectal cancer (CRC) aggressiveness and clinical outcomes in relation to tumor stage and different molecular subsets is at most important for designing treatment regimens. However, molecular signatures for specific phenotypic subsets that predict the aggressiveness and clinical outcomes of CRC, specifically in advanced disease stage are lacking. Therefore, for the first time, the current study has identified a set of molecular markers that are associated with aggressive Stage III CRCs that exhibited microsatellite stable and mutant p53 phenotypic features. These findings might aid in designing aggressive treatment regimens and help to provide insights into the development of novel therapeutic targets. Results: Increased incidence of p53 mutations in MSS CRCs (58%) was associated with higher CRC-specific mortality than MSS-p53 wild-type phenotypes (log-rank, P=0.025; and hazard ratio, 2.52; 95% confidence interval, 1.25-5.08). Of 49 down-regulated genes, LPAR6, PDLIM3 and PLAT and of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8, were confirmed by qNPA, qRT-PCR, and IHC platforms. Conclusions: p53 mutations are associated with poor prognosis of Stage III microsatellite stable CRCs.
Project description:Purpose: The goal of this experiment was to identify differentially expressed miRNAs between colon cancer patients with and without metachronous metastases. Background: Colon cancer prognosis and treatment are currently based on a classification system still showing large heterogeneity in clinical outcome, especially in TNM-stages II-III. Prognostic biomarkers for metastasis risk are warranted, as development of distant recurrent disease mainly accounts for the high lethality rates of colon cancer. MicroRNAs have been proposed as potential biomarkers for cancer. Furthermore, a verified standard for normalization of the amount of input material in PCR-based relative quantification of miRNA expression is lacking. Methods: A selection of frozen tumor specimens from two independent patient cohorts with TNM-stage II-III microsatellite stable primary adenocarcinomas were used for laser capture microdissection. Next-generation sequencing was performed on small RNAs isolated from colorectal tumors from the Dutch cohort (N=50). Differential expression analysis, comparing in metastasized- and non-metastasized tumors, identified prognostic microRNAs. Validation was performed on colon tumors from the German cohort (N=43) using qPCR. Results: MiR-25-3p and miR-339-5p were identified and validated as independent prognostic markers and used to construct a multivariate nomogram for metastasis risk prediction. The nomogram showed good probability prediction in validation. Additionally, we recommend combination of miR-16-5p and miR-26a-5p as standard for normalization in qPCR of colon cancer tissue-derived microRNA expression. Conclusions: In this international study, we identified and validated an miRNA classifier in primary cancers, and propose a nomogram capable of predicting metastasis risk in microsatellite stable TNM-stage II-III colon cancer.
Project description:RATIONALE: Identifying gene mutations (microsatellite instability) may allow doctors to plan effective treatment for patients who develop colorectal cancer at an early age.
PURPOSE: Genetic trial to determine the significance of gene mutations in helping predict the outcome of treatment in patients who develop stage I, stage II, or stage III colorectal cancer at an early age.
Project description:Genomic instability, including microsatellite instability (MSI) and gross chromosomal abnormalities, has been described in sporadic colorectal cancer (CRC) and MSI has been suggested to have prognostic significance. However, there are few prognostically relevant biomarkers. Here we explore the potential of the analysis of DNA copy number changes at 1Mb resolution to predict survivorship in sporadic CRC. Keywords: Comparative Genomic Hybridization
Project description:Gene expression profiles of paired normal adjacent mucosa and tumor samples from 98 individuals and 50 healthy colon mucosae, were obtained through Affymetrix Human Genome U219 Arrays. This dataset is in the context of the COLONOMICS project and to query additional information you can visit the project website www.colonomics.org. Colon tumor and adjacent paired normal mucosa tissues samples used in this study were selected from a series of cases with a new diagnosis of colorectal adenocarcinoma histologically confirmed. Included cases were from a homogenous series of patients with more than three years of follow up, early stage (II), without neoadjuvant chemotherapy and microsatellite stable colon cancer. Additionally, samples of colon mucosa from 50 healthy donors without colonic lesions were obtained during colonoscopy.