Dataset Information

Development and validation of a collagen signature to predict the prognosis of patients with stage II/III colorectal cancer.

ABSTRACT: The tumor, nodes and metastasis (TNM) classification system provides useful but incomplete prognostic information and lacks the assessment of the tumor microenvironment (TME). Collagen, the main component of the TME extracellular matrix, plays a nonnegligible role in tumor invasion and metastasis. In this cohort study, we aimed to develop and validate a TME collagen signature (CS_TME) for prognostic prediction of stage II/III colorectal cancer (CRC) and to compare the prognostic values of "TNM stage + CS_TME" with that of TNM stage alone. Results indicated that the CS_TME was an independent prognostic risk factor for stage II/III CRC (hazard ratio: 2.939, 95% CI: 2.180-3.962, p < 0.0001), and the integration of the TNM stage and CS_TME had a better prognostic value than that of the TNM stage alone (AUC_(TNM+CSTME) = 0.772, AUC _TNM = 0.687, p < 0.0001). This study provided an application of "seed and soil" strategy for prognosis prediction and individualized therapy.

SUBMITTER: Dong S

PROVIDER: S-EPMC10192940 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Development and validation of a collagen signature to predict the prognosis of patients with stage II/III colorectal cancer.

Dong Shumin S Wang Huaiming H Ji Hongli H Hu Yaowen Y Zhao Shuhan S Yan Botao B Wang Guangxing G Lin Zexi Z Zhu Weifeng W Lu Jianping J Cheng Jiaxin J Wu Zhida Z Zhu Qiong Q Zhuo Shuangmu S Chen Gang G Yan Jun J

iScience 20230425 5

The tumor, nodes and metastasis (TNM) classification system provides useful but incomplete prognostic information and lacks the assessment of the tumor microenvironment (TME). Collagen, the main component of the TME extracellular matrix, plays a nonnegligible role in tumor invasion and metastasis. In this cohort study, we aimed to develop and validate a TME collagen signature (CS<sub>TME</sub>) for prognostic prediction of stage II/III colorectal cancer (CRC) and to compare the prognostic values ...[more]

PMID: 37216096

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Project description:BackgroundCurrent preoperative evaluation approaches cannot provide adequate information for the prediction of lymph node (LN) metastasis in colorectal cancer (CRC). Collagen alterations in the tumor microenvironment affect the progression of tumor cells. To more accurately assess the LN status of CRC preoperatively, we developed and validated a collagen signature-based nomogram for predicting LN metastasis in CRC.MethodsIn total, 342 consecutive CRC patients were assigned to the training and validation cohorts. A total of 148 fully quantitative collagen features were extracted based on preoperative biopsies using multiphoton imaging, and the least absolute shrinkage and selection operator method was utilized to construct the collagen signature. A collagen signature-based nomogram was developed by multivariable logistic regression in the training cohort. Nomogram performance was evaluated for its discrimination, calibration, and clinical usefulness and then validated in the validation cohort. The prognostic values of the nomogram were also evaluated.ResultsA seven-feature-based collagen signature was built. We found that the collagen signature showed a significant association with LN metastasis in CRC. Additionally, a nomogram incorporating preoperative tumor differentiation, computed tomography-reported T stage and LN status, carcinoembryonic antigen level, carbohydrate antigen 19-9 level and collagen signature was developed. This nomogram had good discrimination and calibration, with AUROCs of 0.826 and 0.846 in the training and validation cohorts, respectively, and had a sensitivity of 86.5%, a specificity of 68.2%, an accuracy of 76.9%, a negative predictive value of 84.9%, and a positive predictive value of 71.2% for all patients. Compared to the clinicopathological model, which consisted of the clinicopathological risk factors for LN metastasis, the collagen signature-based nomogram demonstrated a significantly improved ability to discriminate LN status. Moreover, a nomogram-predicted high-risk subgroup had remarkably reduced survival compared with that of the low-risk subgroup.ConclusionsThe collagen signature in the tumor microenvironment of preoperative biopsies is an independent predictor for LN metastasis in CRC, and the collagen signature-based nomogram is helpful for tailored treatment and prognostic predictions in CRC preoperatively.

Project description:BackgroundImmune-related genes (IRGs) play important roles in the tumor immune microenvironment and can affect the prognosis of cancer. This study aimed to construct a novel IRG signature for prognostic evaluation of stage II colorectal cancer (CRC).MethodsGene expression profiles and clinical data for stage II CRC patients were collected from the Cancer Genome Atlas and Gene Expression Omnibus database. Univariate, multivariate Cox regression, and least absolute shrinkage and selection operator regression were used to develop the IRG signature, namely IRGCRCII. A nomogram was constructed, and the "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts" (CIBERSORT) method was used to estimate immune cell infiltration. The expression levels of genes and proteins were validated by qRT-PCR and immunohistochemistry in 30 pairs of primary stage II CRC and matched normal tissues.ResultsA total of 466 patients with stage II CRC were included, and 274 differentially expressed IRGs were identified. Six differentially expressed IRGs were detected and used to construct the IRGCRCII signature, which could significantly stratify patients into high-risk and low-risk groups in terms of disease-free survival in three cohorts: training, test, and external validation (GSE39582). Receiver operating characteristics analysis revealed that the area under the curves of the IRGCRCII signature were significantly greater than those of the OncotypeDX colon signature at 1 (0.759 vs. 0.623), 3 (0.875 vs. 0.629), and 5 years (0.906 vs. 0.698) disease-free survival, respectively. The nomogram performed well in the concordance index (0.779) and calibration curves. The high-risk group had a significantly higher percentage of infiltrated immune cells (e.g., M2 macrophages, plasma cells, resting mast cells) than the low-risk group. Finally, the results of qRT-PCR and immunohistochemistry experiments performed on 30 pairs of clinical specimens were consistent with bioinformatics analysis.ConclusionThis study developed and validated a novel immune prognostic signature based on six differentially expressed IRGs for predicting disease-free survival and immune status in patients with stage II CRC, which may reflect immune dysregulation in the tumor immune microenvironment.

Project description:Distant metastasis is the major causes of death in colorectal cancer (CRC) patients. In order to identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real-time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (P < 0.001). In stage II and stage III CRC, patients with low expression showed worse disease-free survival (P = 0.038). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in stage II and stage III CRC (relative risk, 9.532; 95% confidence interval, 2.303-41.905; P = 0.002). This study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients. Total of 111 microarray datasets (77 for LCM samples, and 17 pairs for homogenized samples from tumor and adjacent tissues) were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software together with BioConductor package, as described previously. Then, the gene expression levels were log2-transformed, and 62 control probe sets were removed for further analysis. In order to identify a set of genes associated with development of metastatic recurrence, we performed Wilcoxon rank-sum test for gene expression differences of 54,613 probe sets between recurrence and non-recurrence groups. Similarly, Wilcoxon singed-rank test was conducted to select genes which showed significant expression difference between tumor and adjacent tissue. Then, we selected a set of genes that satisfied both of above two criteria.

Project description:Currently, there is no consensus about the use of adjuvant chemotherapy for patients with stage II colorectal cancer. Here, we aimed to identify and validate a prognostic mRNA expression signature for the stratification of patients with stage II colorectal cancer according to their risk for relapse. First, publicly available mRNA expression profiling datasets from 792 primary, stage II colorectal cancers from six different training cohorts were analyzed to identify genes that are consistently associated with patient relapse-free survival (RFS). Second, the identified gene expression signature was experimentally validated using NanoString technology and computationally refined on primary colorectal cancer samples from 205 patients with stage II colorectal cancer. Third, the refined signature was validated in two independent publicly available cohorts of 166 patients with stage II colorectal cancer. Bioinformatics analysis of training cohorts identified a 61-gene signature that was highly significantly associated with RFS (HR = 37.08, P = 2.68*10-106, sensitivity = 89.29%, specificity = 89.61%, and AUC = 0.937). The experimental validation and refinement revealed a 15-gene signature that robustly predicted relapse in three independent cohorts: an in-house cohort (HR = 20.4, P = 8.73*10-23, sensitivity = 90.32%, specificity = 80.99%, AUC = 0.812), GSE161158 (HR = 5.81, P = 3.57*10-4, sensitivity = 64.29%, specificity = 81.67%, AUC = 0.796), and GSE26906 (HR = 7.698, P = 7.26*10-8, sensitivity = 61.54%, specificity = 78.33%, AUC = 0.752). In the pooled training cohort, the 15-gene signature (HR = 4.72, P = 7.76*10-25, sensitivity = 75%, specificity = 67.44%, AUC = 0.784) was superior to the Oncotype DX colon 7-gene signature (HR = 2.698, P = 6.3*10-8, sensitivity = 62.16%, specificity = 55.5%, AUC = 0.633). We report the identification and validation of a novel mRNA expression signature for robust prognostication and stratification of patients with stage II colorectal cancer, with superior performance in the analyzed validation cohorts when compared with clinicopathologic biomarkers and signatures currently used for stage II colorectal cancer prognostication.SignificanceWe identified and validated a 15-gene expression signature for robust prognostication and stratification of patients with stage II colorectal cancer, with superior performance when compared with currently used biomarkers. Therefore, the 15-gene expression signature has the potential to improve the prognostication and treatment decisions for patients with stage II colorectal cancer.

Dataset Information

Development and validation of a collagen signature to predict the prognosis of patients with stage II/III colorectal cancer.

Publications

Development and validation of a collagen signature to predict the prognosis of patients with stage II/III colorectal cancer.

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