Dataset Information

Calculated identification of mutator-derived lncRNA signatures of genomic instability to predict the clinical outcome of muscle-invasive bladder cancer.

ABSTRACT:

Background

Muscle-invasive bladder cancer (MIBC) is one of the most important type of bladder cancer, with a high morbidity and mortality rate. Studies have found that long non-coding RNA (lncRNA) plays a key role in maintaining genomic instability. However, Identification of lncRNAs related to genomic instability (GIlncRNAs) and their clinical significance in cancers have not been extensively studied yet.

Methods

Here, we downloaded the lncRNA expression profiles, somatic mutation profiles and clinical related data in MIBC patients from The Cancer Genome Atlas (TCGA) database. A lncRNA computational framework was used to find differentially expressed GIlncRNAs. Multivariate Cox regression analysis was used to construct a genomic instability-related lncRNA signature (GIlncSig). Univariate and multivariate Cox analyses were used to assess the independent prognostic for the GIlncSig and other key clinical factors.

Results

We found 43 differentially expressed GIlncRNAs and constructed the GIlncSig with 6 GIlncRNAs in the training cohort. The patients were divided into two risk groups. The overall survival of patients in the high-risk group was lower than that in the low-risk group (P < 0.001), which were further verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression showed that the GIlncSig was an independent prognostic factor. In addition, the GIlncSig correlated with the genomic mutation rate of MIBC, indicating its potential as a measure of the degree of genomic instability. The GIlncSig was able to divide FGFR3 wild- and mutant-type patients into two risk groups, and effectively enhanced the prediction effect.

Conclusion

Our study introduced an important reference for further research on the role of GIlncRNAs, and provided prognostic indicators and potential biological therapy targets for MIBC.

SUBMITTER: Liang Y

PROVIDER: S-EPMC8424867 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIncreasing evidence has emerged to reveal the correlation between genomic instability and long non-coding RNAs (lncRNAs). The genomic instability-derived lncRNA landscape of prostate cancer (PCa) and its critical clinical implications remain to be understood.MethodsPatients diagnosed with PCa were recruited from The Cancer Genome Atlas (TCGA) program. Genomic instability-associated lncRNAs were identified by a mutator hypothesis-originated calculative approach. A signature (GILncSig) was derived from genomic instability-associated lncRNAs to classify PCa patients into high-risk and low-risk groups. The biochemical recurrence (BCR) model of a genomic instability-derived lncRNA signature (GILncSig) was established by Cox regression and stratified analysis in the train set. Then its prognostic value and association with clinical features were verified by Kaplan-Meier (K-M) analysis and receiver operating characteristic (ROC) curve in the test set and the total patient set. The regulatory network of transcription factors (TFs) and lncRNAs was established to evaluate TF-lncRNA interactions.ResultsA total of 95 genomic instability-associated lncRNAs of PCa were identified. We constructed the GILncSig based on 10 lncRNAs with independent prognostic value. GILncSig separated patients into the high-risk (n = 121) group and the low-risk (n = 121) group in the train set. Patients with high GILncSig score suffered from more frequent BCR than those with low GILncSig score. The results were further validated in the test set, the whole TCGA cohort, and different subgroups stratified by age and Gleason score (GS). A high GILncSig risk score was significantly associated with a high mutation burden and a low critical gene expression (PTEN and CDK12) in PCa. The predictive performance of our BCR model based on GILncSig outperformed other existing BCR models of PCa based on lncRNAs. The GILncSig also showed a remarkable ability to predict BCR in the subgroup of patients with TP53 mutation or wild type. Transcription factors, such as FOXA1, JUND, and SRF, were found to participate in the regulation of lncRNAs with prognostic value.ConclusionIn summary, we developed a prognostic signature of BCR based on genomic instability-associated lncRNAs for PCa, which may provide new insights into the epigenetic mechanism of BCR.