Construction of an RNA Binding Protein-based Model for Prognosis Prediction of Colorectal Cancer

Abstract Background: Colorectalcancer (CRC) is a prevalent gastrointestinal tumor with high incidence and mortality. Dysregulation of RNA binding proteins (RBPs) has been found in a variety of cancers and is related to oncogenesis and progression. This study aimed to develop and validate new biomarkers related to CRC prognosis by a series of bioinformatics analysis.Methods: We mined the gene expression data of 510 CRC samples from The Cancer Genome Atlas (TCGA) database, differentially expressed genes were screened and prognosis-related genes were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. A prognosis-related gene signature was constructed by univariate and multivariate Cox analysis. Kaplan–Meier curves and time-dependent receiver operating characteristic (ROC) curves were utilized to evaluate the signature,The test set was used to validate the RBPs risk score model.Survival analysis was carried out to determine the independent prognostic significance of the signature. A nomogram combined with the gene signature was constructed.Results: A total of 224 aberrantly expressed RBPs were obtained, comprising 78 downregulated and 146 upregulatedRBPs. 13 RBPs with p < 0.005 were revealed in univariateCox regression analysis of train group, then stepwise multivariate Cox regression was applied for constituting an eight- RBP (BRCA1, TERT, TDRD7, PPARGC1A, LUZP4, CELF4, ZC3H12C, PNLDC1) signature prognostic biomarkers. Further analysis demonstrated that high risk score for patients was significantly related to poor overall survival according to the model. The area under the time-dependent receiver operator characteristic curve of the prognostic model was 0.730 at 5 years. The signature-based risk score was an independent prognostic factor in CRC patients. We also established a nomogram based on eight RBPs and internal validation in the train set, which displayed a favorable discriminating ability for Colorectal cancer.Conclusions: The established eight-RBP signature may serve as a novel independent prognostic factor that could be an important tool to predict the prognostic outcome of CRC patients. However, the specific biological mechanism needs further verification.

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Core Circadian Clock Proteins as Biomarkers of Progression in Colorectal Cancer

Biomedicines ◽

10.3390/biomedicines9080967 ◽

2021 ◽

Vol 9 (8) ◽

pp. 967

Author(s):

María I. Aroca-Siendones ◽

Sara Moreno-SanJuan ◽

Jose D. Puentes-Pardo ◽

Michela Verbeni ◽

Javier Arnedo ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Prognostic Significance ◽

Developed Countries ◽

Disease Diagnosis ◽

Independent Prognostic Factor ◽

High Expression ◽

Incidence And Mortality ◽

Circadian Clock Proteins ◽

Low Expression

Colorectal cancer (CRC) is one of the most common tumours in developed countries. Although its incidence and mortality rates have decreased, its prognosis has not changed, and a high percentage of patients with CRC develop relapse (metachronous metastasis, MM, or local recurrence, LR) during their disease. The identification of these patients is very important for their correct management, but the lack of prognostic markers makes it difficult. Given the connection between circadian disruption and cancer development and progression, we aimed to analyse the prognostic significance of core circadian proteins in CRC. We measured the expression of PER1-3, CRY1-2, BMAL1 and NR1D2 in a cohort of CRC patients by immunohistochemistry (IHC) and analysed their prognostic potential in this disease. A low expression of PER2 and BMAL1 was significantly associated with metastasis at the moment of disease diagnosis, whereas a high expression of CRY1 appeared as an independent prognostic factor of MM development. A high expression of NR1D2 appeared as an independent prognostic factor of LR development after disease diagnosis. Moreover, patients with a low expression of BMAL1 and a high expression of CRY1 showed lower OS and DFS at five years. Although these markers need to be validated in larger and different ethnic cohorts, the simplicity of IHC makes these proteins candidates for personalizing CRC treatment.

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Chemokine (C-X-C motif) ligand 1 is associated with tumor progression and poor prognosis in patients with colorectal cancer

Bioscience Reports ◽

10.1042/bsr20180580 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 15

Author(s):

Changhua Zhuo ◽

Xianyi Wu ◽

Jing Li ◽

Dan Hu ◽

Jinliang Jian ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Cancer Progression ◽

Cox Regression ◽

Prognostic Significance ◽

Disease Free Survival ◽

Independent Prognostic Factor ◽

In Vitro Assays ◽

Tumor Diameter ◽

Cxcl1 Expression

Chemokine (C-X-C motif) ligand 1 (CXCL1) is a chemotactic cytokine known to regulate cancer progression and invasion. However, the prognostic significance of CXCL1 expression in colorectal cancer (CRC) has not been fully characterized. The present study explored the clinicopathological significance and potential role of CXCL1 in the carcinogenesis and progression of CRC. The protein expression of CXCL1 was measured immunohistochemically in tissue microarrays constructed from 276 CRC patients. CXCL1 expression levels and their associations with clinicopathological characteristics and patient survival were evaluated. The effect of CXCL1 on glycolysis was also examined. High CXCL1 expression was detected in 165 (59.8%) cases. CXCL1 expression was correlated with tumor diameter (P=0.002), T stage (P=0.044), N stage (P=0.005), M stage (P=0.001), lymphovascular invasion (P=0.010), and carcinoembryonic antigen status (P=0.019). High CXCL1 expression was validated as an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) by both univariate and multivariate Cox regression analyses (both P<0.05). Experimentally, expression of CXCL1 was knocked down by stable transfected short hairpin RNA, resulting in a significantly decreased rate of glycolysis both in in vitro assays and in patients’ samples (P<0.05). Silencing the expression of CXCL1 decreased the levels of the glycolytic enzymes GLUT1, HK2, and LDHA. In conclusion, by inducing glycolysis, CXCL1 plays a crucial role in both cancer progression and metastasis in CRC patients. The CXCL1 expression level is an independent prognostic factor for both OS and DFS. Moreover, CXCL1 may serve as a new biomarker and potential therapeutic target for CRC treatment.

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Circulating Fibrinogen to Pre-albumin Ratio for Chemotherapy Efficacy Prediction and Prognosis of Colorectal Cancer Patients

10.21203/rs.3.rs-45688/v1 ◽

2020 ◽

Author(s):

Hou-Qun Ying ◽

Fan Sun ◽

Wei Wang ◽

Dan Cai ◽

Ying Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Chronic Inflammation ◽

Clinical Outcomes ◽

Cox Regression ◽

Independent Prognostic Factor ◽

Low Grade ◽

Albumin Ratio ◽

Response To Chemotherapy ◽

Chemotherapy Efficacy

Abstract Background Evaluating chronic inflammation in colorectal cancer (CRC) may aid in identifying patients at the highest risk of recurrence or progression, and help inform clinical treatment decisions. Here, we report the effect of fibrinogen to pre-albumin ratio (FPR) in determining response to chemotherapy and reveal outcomes in CRC patients. Methods A total of 2917 eligible CRC patients from multiple-centers were enrolled, and the outcome of these patients was obtained by three years’ follow-up. Circulating fibrinogen, albumin, pre-albumin, CEA, CA199 and FPR were detected and calculated in these patients. Kaplan-Meier curves, Cox regression, time-dependent ROC, Harrell’s concordance index, calibration and decision curves were used to investigate the role of FPR in clinical outcome of CRC patients. Results Our results reveal significantly inferior outcomes in right- than left-sided patients with advanced CRC (stage III and IV), with preoperative FPR found to be a robust and independent prognostic factor for CRC at each stage. Moreover, prognostic nomograms, including FPR, effectively predicted clinical outcomes of the patients. Furthermore, preoperative FPR was significantly associated with chemotherapy efficacy. Specifically, low-grade (FPR < 15) and medium-grade (15 ≤ FPR < 20) FPR patients exhibited complete response to chemotherapy and attenuated chemosensitivity, respectively, whereas high-grade inflammation (FPR ≥ 20) conferred resistance to the treatment. Conclusion CRC-related inflammation affects response to chemotherapy and the resultant clinical outcomes. Circulating FPR is a simple, economically-friendly and robust independent prognostic factor for effectively predicting outcomes of CRC patients. Targeting chronic inflammation and its corresponding signaling pathway, coupled with measuring FPR, presents a novel approach for clinical management of CRC.

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Prognostic Significance of Sarcopenia in Patients with Unresectable Advanced Esophageal Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8101647 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1647 ◽

Cited By ~ 5

Author(s):

Sachiyo Onishi ◽

Masahiro Tajika ◽

Tsutomu Tanaka ◽

Yutaka Hirayama ◽

Kazuo Hara ◽

...

Keyword(s):

Esophageal Cancer ◽

Prognostic Factor ◽

Cox Regression ◽

Prognostic Significance ◽

Japanese Patients ◽

Independent Prognostic Factor ◽

Cancer Center ◽

Advanced Esophageal Cancer ◽

Cox Regression Analysis ◽

Group 2

The prognostic significance of sarcopenia in unresectable advanced esophageal cancer remains unclear. Our study retrospectively evaluated 176 consecutive Japanese patients with esophageal squamous cell carcinoma who had been diagnosed with unresectable advanced cancer in Aichi Cancer Center Hospital between January 2007 and December 2014. Skeletal muscle mass was calculated from abdominal computed tomography (CT) scans before treatment, and patients were divided into sarcopenic and non-sarcopenic groups. Sarcopenia was present in 101 patients (57.4%). Eighty-two patients in the sarcopenic group and 63 patients in the non-sarcopenic group died during follow-up (mean: 20.3 months). The overall survival (OS) rate was significantly lower in the sarcopenic group compared to the non-sarcopenic group (2-year OS: 9.8% vs. 23.7%, p < 0.01). Cox regression analysis revealed only pretreatment sarcopenia as an independent prognostic factor (hazard ratio (HR): 1.48, 95% confidence interval (CI): 1.04–2.10, p = 0.03). In the sarcopenic group, withdrawn cases, for whom the planned treatment was discontinued for some reason, showed a significantly lower OS rate compared to complete cases (1-year OS: 11.0% vs. 59.9%, p < 0.01). The most common reason for discontinuation was aspiration pneumonia (64.5%). Presence of sarcopenia was an independent prognostic factor for unresectable advanced esophageal cancer. Identifying the presence of sarcopenia prior to treatment may improve the prognosis.

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RNA Binding Protein-Based Model for Prognostic Prediction of Colorectal Cancer

Technology in Cancer Research & Treatment ◽

10.1177/15330338211019504 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110195

Author(s):

Ting Li ◽

Wenjia Hui ◽

Halina Halike ◽

Feng Gao

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Rna Binding ◽

Cox Regression ◽

Rna Binding Proteins ◽

Differential Expression Analysis ◽

High Morbidity ◽

Sw620 Cell ◽

Cox Regression Analysis ◽

Qrt Pcr

Background: Colorectal cancer (CRC) is a kind of gastrointestinal tumor with serious high morbidity and mortality. Several reports have implicated the disorder of RNA-binding proteins (RBPs) in plenty of tumors, associating it to tumorigenesis and disease progression. The study is intended to construct novel prognostic biomarkers associated with CRC patients. Methods: Data of gene expression was acquired from the TCGA database, prognosis-related genes were selected. Besides, we analyzed GO and KEGG pathways. Univariate and multivariate Cox analyses were performed to generate a prognostic-related gene signature, which was evaluated by the Kaplan-Meier (K-M) and the Receiver Operating Characteristic (ROC) curve. The independent prognostic factor was established by survival analysis. GSE38832 dataset was used to validate the signature. Finally, expression of 8 genes was further confirmed by qRT-PCR in SW480 and SW620 cell lines. Results: We obtained 224 differentially expressed RBPS in total, of which 78 were downregulated and 146 were upregulated. Univariate COX analysis was conducted in the TCGA cohort to select 13 RBPs with P < 0.005, stepwise multivariate COX regression analysis was used to construct an 8—RBP signature (TERT, PPARGC1A, BRCA1, CELF4, TDRD7, LUZP4, PNLDC1, ZC3H12C). Based on the model, systematic analysis illustrated that a high risk score was obviously connected to a poor prognosis. The prognostic value of the risk score was validated in GSE38832 dataset, indicating that the risk model was accurate and effective. The prognostic signature-based risk score was identified as an independent prognostic indicator for CRC. The expression results of qRT-PCR were consistent with the results of differential expression analysis. Conclusions: The eight-RBP signature can predict the survival of CRC patients and potentially act as CRC prognostic biomarker.

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Identification of a Novel Glycolysis-Related Signature to Predict the Prognosis of Patients with Breast Cancer

10.21203/rs.3.rs-720991/v1 ◽

2021 ◽

Author(s):

Menglin He ◽

Cheng Hu ◽

Jian Deng ◽

Hui Ji ◽

Weiqian Tian

Keyword(s):

Breast Cancer ◽

Risk Score ◽

Cox Regression ◽

Risk Group ◽

Gene Signature ◽

High Risk Group ◽

Low Risk ◽

Cox Regression Analysis ◽

Expression Levels ◽

Incidence And Mortality

Abstract Background: Breast cancer (BC) is a kind of cancer with high incidence and mortality in female. Conventional clinical characteristics are far from accurate to predict individual outcomes. Therefore, we aimed to develop a novel signature to predict the survival of patients with BC. Methods: We analyzed the data of a training cohort from the TCGA database and a validation cohort from GEO database. After the applications of GSEA and Cox regression analyses, a glycolysis-related signature for predicting the survival of patients with BC was developed. The signature contains AK3, CACNA1H, IL13RA1, NUP43, PGK1, and SDC1. Then, we constructed a risk score formula to classify the patients into high and low-risk groups based on the expression levels of six-gene in patients. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to assess the predicted capacity of the model. Next, a nomogram was developed to predict the outcomes of patients with risk score and clinical features in 1, 3, and 5 years. We further used Human Protein Atlas (HPA) database to validate the expressions of the six biomarkers in tumor and sample tissues.Results: We constructed a six-gene signature to predict the outcomes of patients with BC. The patients in high-risk group showed poor prognosis than that in low-risk group. The AUC values were 0.719 and 0.702, showing that the prediction performance of the signature is acceptable. Additionally, Cox regression analysis revealed that these biomarkers could independently predict the prognosis of BC patients without being affected by clinical factors. The expression levels of all six biomarkers in BC tissues were higher than that in normal tissues except AK3. Conclusion: We developed a six-gene signature to predict the prognosis of patients with BC. Our signature has been proved to have the ability to make an accurate and obvious prediction and might be used to expand the prediction methods in clinical.

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Fibronectin and Periostin as Prognostic Markers in Ovarian Cancer

Cells ◽

10.3390/cells9010149 ◽

2020 ◽

Vol 9 (1) ◽

pp. 149 ◽

Cited By ~ 4

Author(s):

Katarzyna Aleksandra Kujawa ◽

Ewa Zembala-Nożyńska ◽

Alexander Jorge Cortez ◽

Tomasz Kujawa ◽

Jolanta Kupryjańczyk ◽

...

Keyword(s):

Ovarian Cancer ◽

Prognostic Factor ◽

Prognostic Markers ◽

Cox Regression ◽

Prognostic Significance ◽

Advanced Ovarian Cancer ◽

Independent Prognostic Factor ◽

Benign Tumors ◽

Molecular Features ◽

Kaplan Meier

Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was aimed to validate two proteins, namely fibronectin (FN1) and periostin (POSTN), in the independent set of ovarian cancer samples. Both proteins are mainly known as extracellular matrix proteins with many important functions in physiology. However, there are also indications that they are implicated in cancer, including ovarian cancer. The expression of these proteins was immunohistochemically analyzed in 108 surgical samples of advanced ovarian cancer (majority: high-grade serous) and additionally on tissue arrays representing different stages of the progression of ovarian and fallopian tube epithelial tumors, from normal epithelia, through benign tumors, to adenocarcinomas of different stages. The correlation with clinical, pathological, and molecular features was evaluated. Kaplan–Meier survival analysis and Cox-proportional hazards models were used to estimate the correlation of the expression levels these proteins with survival. We observed that the higher expression of fibronectin in the tumor stroma was highly associated with shorter overall survival (OS) (Kaplan–Meier analysis, log-rank test p = 0.003). Periostin was also associated with shorter OS (p = 0.04). When we analyzed the combined score, calculated by adding together individual scores for stromal fibronectin and periostin expression, Cox regression demonstrated that this joint FN1&POSTN score was an independent prognostic factor for OS (HR = 2.16; 95% CI: 1.02–4.60; p = 0.044). The expression of fibronectin and periostin was also associated with the source of ovarian tumor sample: metastases showed higher expression of these proteins than primary tumor samples (χ2 test, p = 0.024 and p = 0.032). Elevated expression of fibronectin and periostin was also more common in fallopian cancers than in ovarian cancers. Our results support some previous observations that fibronectin and periostin have a prognostic significance in ovarian cancer. In addition, we propose the joint FN1&POSTN score as an independent prognostic factor for OS. Based on our results, it may also be speculated that these proteins are related to tumor progression and/or may indicate fallopian–epithelial origin of the tumor.

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The lymphocyte to monocyte ratio in peripheral blood represents a novel prognostic marker in patients with pancreatic cancer

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0447 ◽

2015 ◽

Vol 53 (3) ◽

Cited By ~ 40

Author(s):

Michael Stotz ◽

Joanna Szkandera ◽

Tatjana Stojakovic ◽

Julia Seidel ◽

Hellmut Samonigg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Prognostic Factor ◽

Peripheral Blood ◽

Cox Regression ◽

Univariate Analysis ◽

Prognostic Significance ◽

Tumor Grade ◽

Tumor Stage ◽

Independent Prognostic Factor ◽

Lymphocyte To Monocyte Ratio

AbstractIntra-tumoral macrophages have been involved as important players in the pathogenesis and progression of cancer. Recently, inflammatory parameters of the systemic inflammatory response have also been proposed as usefully prognostic biomarkers. One of these, the lymphocyte to monocyte ratio (LMR) in peripheral blood has been shown as a prognostic factor in hematologic and some solid tumors. In this study we analyzed for the first time the prognostic value of LMR in a large middle European cohort of pancreatic cancer (PC) patients.Data from 474 consecutive patients with ductal adenocarcinoma of the pancreas were evaluated retrospectively. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. To further evaluate the prognostic significance of the LMR, univariate and multivariate Cox regression models were calculated.Increased LMR at diagnosis was significantly associated with well-established prognostic factors, including high tumor stage and tumor grade (p<0.05). In univariate analysis, we observed that an increased LMR was a significant factor for better CSS in PC patients (HR 0.70; 95% CI 0.57–0.85; p<0.001). In multivariate analysis including age, Karnofsky Index, tumor grade, tumor stage, administration of chemotherapy, LMR and surgical resection, we confirmed increased LMR as an independent prognostic factor for CSS (HR 0.81; 95% CI 0.66–0.99; p=0.04).In conclusion, we identified LMR as an independent prognostic factor in PC patients. Our results indicate that the LMR might represent a novel and useful marker for patient stratification in PC management.

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The AST/ALT (De Ritis) Ratio Predicts Survival in Patients with Oral and Oropharyngeal Cancer

Diagnostics ◽

10.3390/diagnostics10110973 ◽

2020 ◽

Vol 10 (11) ◽

pp. 973

Author(s):

Olivia Knittelfelder ◽

Daniela Delago ◽

Gabi Jakse ◽

Sabine Reinisch ◽

Richard Partl ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factor ◽

Cox Regression ◽

Cell Cancer ◽

Survival Rates ◽

Prognostic Significance ◽

Independent Prognostic Factor ◽

Operating Characteristics ◽

Roc Curve Analysis ◽

Cancer Specific Survival

Aminotransaminases, including aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), are strongly involved in cancer cell metabolism and have been associated with prognosis in different types of cancer. The purpose of the present study was to evaluate the prognostic significance of the pre-treatment AST/ALT ratio in a large European cohort of patients with oral and oropharyngeal squamous cell cancer (OOSCC). Data from 515 patients treated for OOSCC at a tertiary academic center from 2000–2017 were retrospectively analyzed. Levels of AST and ALT were measured prior to the start of treatment. Uni- and multivariate Cox regression analyses were applied to evaluate the prognostic value of the AST/ALT ratio for cancer-specific survival (CSS) and overall survival (OS), survival rates were calculated. Univariate analyses showed a significant association of the AST/ALT ratio with CSS (hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.38–2.12; p < 0.001) and OS (HR 1.69, 95% CI 1.41–2.02; p < 0.001). In multivariate analysis, the AST/ALT ratio remained an independent prognostic factor for CSS and OS (HR 1.45, 95% CI 1.12–1.88, p = 0.005 and HR 1.42, 95% CI 1.14–1.77, p = 0.002). Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the AST/ALT ratio was 1.44, respectively. In multivariate analysis, an AST/ALT ratio > 1.44 was an independent prognostic factor for poor CSS and OS (HR 1.64, 95% CI 1.10–2.43, p = 0.014 and HR 1.55, 95% CI 1.12–2.15; p = 0.008). We conclude that the AST/ALT ratio is a prognostic marker for survival in OOSCC patients and could contribute to a better risk stratification and improved oncological therapy decisions.

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Identification of Five Glycolysis-Related Gene Signature and Risk Score Model for Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.588811 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jun Zhu ◽

Shuai Wang ◽

Han Bai ◽

Ke Wang ◽

Jun Hao ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Risk Model ◽

Cox Regression ◽

Aerobic Glycolysis ◽

Gene Clusters ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

Calibration Plot ◽

Relationship Of

Metabolic changes, especially in glucose metabolism, are widely established during the occurrence and development of tumors and regarded as biological markers of pan-cancer. The well-known ‘Warburg effect’ demonstrates that cancer cells prefer aerobic glycolysis even if there is sufficient ambient oxygen. Accumulating evidence suggests that aerobic glycolysis plays a pivotal role in colorectal cancer (CRC) development. However, few studies have examined the relationship of glycolytic gene clusters with prognosis of CRC patients. Here, our aim is to build a glycolysis-associated gene signature as a biomarker for colorectal cancer. The mRNA sequencing and corresponding clinical data were downloaded from TCGA and GEO databases. Gene set enrichment analysis (GSEA) was performed, indicating that four gene clusters were significantly enriched, which revealed the inextricable relationship of CRC with glycolysis. By comparing gene expression of cancer and adjacent samples, 236 genes were identified. Univariate, multivariate, and LASSO Cox regression analyses screened out five prognostic-related genes (ENO3, GPC1, P4HA1, SPAG4, and STC2). Kaplan–Meier curves and receiver operating characteristic curves (ROC, AUC = 0.766) showed that the risk model could become an effective prognostic indicator (P < 0.001). Multivariate Cox analysis also revealed that this risk model is independent of age and TNM stages. We further validated this risk model in external cohorts (GES38832 and GSE39582), showing these five glycolytic genes could emerge as reliable predictors for CRC patients’ outcomes. Lastly, based on five genes and risk score, we construct a nomogram model assessed by C-index (0.7905) and calibration plot. In conclusion, we highlighted the clinical significance of glycolysis in CRC and constructed a glycolysis-related prognostic model, providing a promising target for glycolysis regulation in CRC.

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