A potential prognostic long non-coding RNA signature to predict metastasis-free survival of breast cancer patients.
ABSTRACT: Long non-coding RNAs (lncRNAs) have been implicated in a variety of biological processes, and dysregulated lncRNAs have demonstrated potential roles as biomarkers and therapeutic targets for cancer prognosis and treatment. In this study, by repurposing microarray probes, we analyzed lncRNA expression profiles of 916 breast cancer patients from the Gene Expression Omnibus (GEO). Nine lncRNAs were identified to be significantly associated with metastasis-free survival (MFS) in the training dataset of 254 patients using the Cox proportional hazards regression model. These nine lncRNAs were then combined to form a single prognostic signature for predicting metastatic risk in breast cancer patients that was able to classify patients in the training dataset into high- and low-risk subgroups with significantly different MFSs (median 2.4 years versus 3.0 years, log-rank test p < 0.001). This nine-lncRNA signature was similarly effective for prognosis in a testing dataset and two independent datasets. Further analysis showed that the predictive ability of the signature was independent of clinical variables, including age, ER status, ESR1 status and ERBB2 status. Our results indicated that lncRNA signature could be a useful prognostic marker to predict metastatic risk in breast cancer patients and may improve upon our understanding of the molecular mechanisms underlying breast cancer metastasis.
Project description:Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes and diseases such as cancer; however, their functions remain poorly characterised. Several studies have demonstrated that lncRNAs are typically disease and tumour subtype specific, particularly in breast cancer where lncRNA expression alone is sufficient to discriminate samples based on hormone status and molecular intrinsic subtype. However, little attempt has been made to assess the reproducibility of lncRNA signatures across more than one dataset. In this work, we derive consensus lncRNA signatures indicative of breast cancer subtype based on two clinical RNA-Seq datasets: the Utah Breast Cancer Study and The Cancer Genome Atlas, through integration of differential expression and hypothesis-free clustering analyses. The most consistent signature is associated with breast cancers of the basal-like subtype, leading us to generate a putative set of six lncRNA basal-like breast cancer markers, at least two of which may have a role in cis-regulation of known poor prognosis markers. Through in silico functional characterization of individual signatures and integration of expression data from pre-clinical cancer models, we discover that discordance between signatures derived from different clinical cohorts can arise from the strong influence of non-cancerous cells in tumour samples. As a consequence, we identify nine lncRNAs putatively associated with breast cancer associated fibroblasts, or the immune response. Overall, our study establishes the confounding effects of tumour purity on lncRNA signature derivation, and generates several novel hypotheses on the role of lncRNAs in basal-like breast cancers and the tumour microenvironment.
Project description:Growing evidence suggests that immune-related genes (IRGs) and long non-coding RNAs (lncRNAs) can serve as prognostic markers of overall survival (OS) in patients with colon cancer. This study aimed to identify an immune-related lncRNA signature for the prospective assessment of prognosis in these patients. Gene expression and clinical data of colon cancer patients were downloaded from The Cancer Genome Atlas (TCGA). Immune-related lncRNAs were identified by a correlation analysis between IRGs and lncRNAs. In total, 447 samples were divided into a training cohort (224 samples) and a testing cohort (223 samples). Univariate, lasso and multivariate Cox regression analyses identified an immune-related nine-lncRNA signature closely related to OS in colon cancer patients in the training dataset. A risk score formula involving nine immune-related lncRNAs was developed to evaluate the prognostic value of the lncRNA signature in the training dataset. Colon cancer patients with a high risk score had poorer OS than those with a low risk score. A multivariate Cox regression analysis confirmed that the immune-related nine-lncRNA signature could be an independent prognostic factor in colon cancer patients. The results were further confirmed in the testing cohort and the entire TCGA cohort. Furthermore, a gene set enrichment analysis revealed several pathways with significant enrichment in the high- and low-risk groups that may be helpful in formulating clinical strategies and understanding the underlying mechanisms. Finally, a quantitative real-time polymerase chain reaction assay found that the nine lncRNAs were significantly differentially expressed in colon cancer cell lines. The results of this study indicate that this signature has important clinical implications for improving predictive outcomes and guiding individualized treatment in colon cancer patients. These lncRNAs could be potential biomarkers affecting the prognosis of colon cancer.
Project description:Dysregulated expression of lncRNAs has been observed in various human complex diseases (including cancers) by recent transcriptional profiling studies, highlighting potentials of lncRNAs as biomarkers for cancer diagnosis and prognosis. Despite some efforts have been made to search for novel lncRNA signature in breast cancer, the prognostic value of lncRNAs for ER-positive breast cancer patients still needs to be systematically investigated. In this study, we analyzed lncRNA expression profiles in a large of more than 600 breast cancer patients with ER-positive status from The Cancer Genome Atlas (TCGA) and identified six lncRNAs that are significantly associated with survival. Then a linear risk score model comprising six prognostic lncRNAs, termed six-lncRNA signature, was developed to identify high-risk patients from low-risk cases. The results of Kaplan-Meier analysis and ROC curves demonstrated the good sensitivity and specificity in survival prediction both in the training and testing datasets. Multivariate Cox regression analysis and stratified analysis showed that the six-lncRNA signature is an independent prognostic marker in survival prediction for ER-positive breast cancer patients. The GO enrichment analysis suggested that the six-lncRNA might involve with known breast cancer-related biological processes. With further experimental validation, these identified prognostic lncRNAs might have clinical implications for more personalized risk assessment for ER-positive breast cancer patients.
Project description:The poor outcome of patients with esophageal squamous cell carcinoma (ESCC) highlights the importance of the identification of novel effective prognostic biomarkers. Long non?coding RNAs (lncRNAs) serve regulatory roles in various types of cancer. The aim of the present study was to investigate the lncRNA expression profile in ESCC and to identify lncRNAs associated with the prognosis of ESCC by performing comprehensive bioinformatics analyses. The RNA?sequencing (Seq) expression dataset GSE53625 generated from ESCC samples was used as a training dataset. Additional RNA?Seq datasets relative to ESCC samples were downloaded from The Cancer Genome Atlas and used as a validation dataset. Data were screened using the limma package, and differentially expressed lncRNAs between early? and late?stage ESCC were identified. A random forest algorithm was used to select the optimal lncRNA biomarkers, which were then analyzed using the support vector machine (SVM) algorithm with R software. The identified lncRNA biomarkers were examined in the validation dataset by bidirectional hierarchical clustering and using an SVM classifier. Subsequently, univariate and multivariate Cox regression analyses were performed to analyze the potential ability lncRNAs to predict the survival rate of patients with ESCC. By examining the training group, 259 deregulated lncRNAs between early? and advanced?stage ESCC were identified. Further bioinformatics analyses identified a nine?lncRNA signature, including AC098973, AL133493, RP11?51M24, RP11?317N8, RP11?834C11, RP11?69C17, LINC00471, LINC01193 and RP1?124C. This nine?lncRNA signature was used to predict the tumor stage and patient survival rate with high reliability and accuracy in the training and validation datasets. Furthermore, these nine lncRNA biomarkers were primarily involved in regulating the cell cycle and DNA replication, and these processes were previously identified to be associated with the progression of ESCC. The identified nine?lncRNA signature was identified to be associated with the tumor stage, and could be used as predictor of the survival rate of patients with ESCC.
Project description:Long non-coding RNAs (lncRNAs) have been demonstrated to be aberrantly expressed in several types of tumor, and dysregulated lncRNAs are suggested to play a prognostic role in breast cancer (BC). Estrogen receptor (ER) status is a prognostic factor in patients with ER-negative BC, which is associated with poor prognosis. Thus, the present study developed a prognostic lncRNA signature specifically for ER-negative BC, in order to predict the risk of post-surgery relapse and improve patient prognosis. A gene expression profile containing 1,631 lncRNAs was obtained by investigating and integrating publicly available cohorts of BC. Subsequently, a nine-lncRNA signature was developed and validated in two independent cohorts via the Cox regression model. Using the nine-lncRNA signature, patients in the discovery cohort were divided into high- and low-risk groups, with significantly different disease-free survival [DFS; hazard ratio (HR)=2.718, 95% confidence interval (CI)=2.115-3.494, P<0.0001]. Receiver operating characteristic curve analyses demonstrated that the area under the curve reached 0.908. Similar results were obtained in the two independent cohorts (HR=1.499, 95% CI=0.950-2.365, P=0.04; HR=1.262, 95% CI=1.056-1.510, P=0.01), respectively. Furthermore, the nine lncRNAs were demonstrated to play important roles in the cell invasion and metastasis of different types of tumor. The differentially expressed genes (DEGs) identified between the high- and low-risk groups were consistently high in the discovery and validation cohorts. Functional analysis indicated that these DEGs, as well as genes co-expressed with the nine lncRNAs, were involved in cancer-associated signaling pathways, all of which provide further evidence for the predictive ability of the nine-lncRNA signature. Overall, the present study developed a novel prognostic biomarker for ER-negative BC.
Project description:<h4>Background</h4>The purpose of this study is to develop an effective but concise long non-coding RNA (lncRNA) expression signature that can predict response to neoadjuvant chemotherapy for breast cancer (BC) patients.<h4>Methods</h4>lncRNA expression profiling in 1102 BC patients from Gene Expression Omnibus datasets was analyzed using lncRNA-mining approach. The association between lncRNA signature and pathological complete response (pCR) was analyzed using logistic regression model in the training set (GSE25066, <i>n</i> = 488). Validation was performed in independent testing datasets, GSE20194, GSE20271, GSE22093, and GSE23988 (<i>n</i> = 614). Bonferroni method was employed for multiple testing corrections. Cell proliferation assay and Western blot assay were performed to evaluate the cell viability and protein expression level, respectively.<h4>Results</h4>Three lncRNAs (AK291479, U79293, and BC032585) have been identified to be significantly associated with pCR in the training dataset (Bonferroni <i>p</i>-value < 0.05). Expression signature with these lncRNAs was predictive of pCR in the training (AUC = 0.74) and testing (AUC = 0.72) datasets. Weighted gene co-expression network analysis and gene functional annotation suggest that the three lncRNAs were involved in cell cycle process. To confirm the functional significance of the identified lncRNAs, BC032585 was selectively silenced using RNA interference. Knockdown of BC032585 lncRNA significantly promoted cell resistance to multiple anticancer-drugs through upregulating MDR1 expression in breast cancer cells.<h4>Conclusion</h4>These results suggest that lncRNAs such as BC032585 might be involved in chemotherapeutic response in breast cancer patients, and the three-lncRNA signature identified in the present study may serve as a useful biomarker for the selection of responsive breast cancer patients in neoadjuvant chemotherapy.
Project description:Mounting evidence suggests that long noncoding RNAs (lncRNAs) are closely related to pathological complete response (pCR) in neoadjuvant treatment of breast cancer. Here, we construct lncRNA associated models to predict pCR rate.LncRNA expression profiles of breast cancer patients treated with neoadjuvant chemotherapy (NAC) were obtained from Gene Expression Omnibus by repurposing existing microarray data. The prediction model was firstly built by analyzing the correlation between pCR and lncRNA expression in the discovery dataset GSE 25066 (n=488). Another three independent datasets, GSE20194 (n=278), GSE20271 (n=178), and GSE22093 (n=97), were integrated as the validation cohort to assess the prediction efficiency.A novel lncRNA signature (LRS) consisting of 36 lncRNAs was identified. Based on this LRS, patients with NAC treatment were divided into two groups: LRS-high group and LRS-low group, with positive correlation of pCR rate in the discovery dataset. In the validation cohort, univariate and multivariate analyses both demonstrated that high LRS was associated with higher pCR rate. Subgroup analysis confirmed that this model performed well in luminal B [odds ratio (OR)=5.4; 95% confidence interval (CI)=2.7-10.8; P=1.47e-06], HER2-enriched (OR=2.5; 95% CI=1.1-5.7; P=.029), and basal-like (OR=5.5; 95% CI=2.3-16.2; P=5.32e-04) subtypes. Compared with other preexisting prediction models, LRS demonstrated better performance with higher area under the curve. Functional annotation analysis suggested that lncRNAs in this signature were mainly involved in cancer proliferation process.Our findings indicated that our lncRNA signature was sensitive to predict pCR rate in the neoadjuvant treatment of breast cancer, which deserves further evaluation.
Project description:Long noncoding RNAs (lncRNAs) play a crucial role in tumorigenesis. The aim of this study is to identify lncRNA signature that can predict breast cancer patient survival. RNA expression data from 1064 patients were downloaded from The Cancer Genome Atlas project. Cox regression, Kaplan-Meier, and receiver operating characteristic (ROC) analyses were performed to construct a model for predicting the overall survival (OS) of patients and evaluate it. A model consisting of three lncRNA genes (CAT104, LINC01234, and STXBP5-AS1) was identified. The Kaplan-Meier analysis and ROC curves proved that the model could predict the prognostic survival with good sensitivity and specificity in both the validation set (AUC?=?0.752, 95% confidence intervals (CI): 0.651-0.854) and the microarray dataset (AUC?=?0.714, 95%CI: 0.615-0.814). Further study showed the three-lncRNA signature was not only pervasive in different breast cancer stages, subtypes and age groups, but also provides more accurate prognostic information than some widely known biomarkers. The results suggested that RNA-seq transcriptome profiling provides that the three-lncRNA signature is an independent prognostic biomarker, and have clinical significance. In addition, lncRNA, miRNA, and mRNA interaction network indicated lncRNAs may intervene in breast cancer pathogenesis by binding to miR-190b, acting as competing endogenous RNAs.
Project description:Long non-coding RNAs (lncRNAs) were reported to have the potential in maintaining genome instability, but the identification of lncRNAs related to genome instability and their prognostic value have not been largely explored in colon cancer. In this study, we obtained 155 genome instability-associated lncRNAs based on somatic mutation profiles in colon cancer from The Cancer Genome Atlas (TCGA) database. Functional enrichment analysis revealed the possible roles of genes co-expressed with those lncRNAs involved in some cancer, genome instability and immune related biological processes. Combined with overall survival data, a seven-lncRNA signature was established for prognosis prediction. According to the risk score calculated by this signature, high-risk patients characterized by high somatic mutation count, high microsatellite instability, significantly poorer clinical outcomes and specific tumor immune infiltration status compared with low-risk patients. The lncRNA signature was validated to be an independent prognostic indicator with good predictive performance in TCGA cohort. Furthermore, the prognostic value of the ZNF503-AS1 in lncRNA signature was confirmed in another independent dataset from Gene Expression Omnibus database. In summary, the genome instability-associated lncRNA signature in this study could be a promising tool for effectively predicting survival outcomes in colon cancer.
Project description:Autophagy-related long non-coding RNAs (lncRNAs) disorders are related to the occurrence and development of breast cancer. The purpose of this study is to explore whether autophagy-related lncRNA can predict the prognosis of breast cancer patients. The autophagy-related lncRNAs prognostic signature was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. We identified five autophagy-related lncRNAs (MAPT-AS1, LINC01871, AL122010.1, AC090912.1, AC061992.1) associated with prognostic value, and they were used to construct an autophagy-related lncRNA prognostic signature (ALPS) model. ALPS model offered an independent prognostic value (HR = 1.664, 1.381-2.006), where this risk score of the model was significantly related to the TNM stage, ER, PR and HER2 status in breast cancer patients. Nomogram could be utilized to predict survival for patients with breast cancer. Principal component analysis and Sankey Diagram results indicated that the distribution of five lncRNAs from the ALPS model tends to be low-risk. Gene set enrichment analysis showed that the high-risk group was enriched in autophagy and cancer-related pathways, and the low-risk group was enriched in regulatory immune-related pathways. These results indicated that the ALPS model composed of five autophagy-related lncRNAs could predict the prognosis of breast cancer patients.