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Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer.

ABSTRACT: Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic value of AS in GBC and the regulatory network of AS in GBC, which may highlight the mechanism through which AS contributes to GBC. In the present study, we obtained splicing event information (SpliceSeq) and clinical information for GBC from The Cancer Genome Atlas, and we constructed a GBC prognosis model based on AS events to predict the survival outcomes of GBC. Kaplan-Meier analysis was conducted to evaluate the predictive accuracy among different molecular subtypes of GBC. We conducted enrichment analysis and constructed a splicing network between AS and the splicing factor (SF) to examine the possible regulatory mechanisms of AS in GBC. We constructed eight prognostic signatures with very high statistical accuracy in predicting GBC survival outcomes from 45,421 AS events of 10,480 genes detected in 462 GBC patients; the prognostic model based on exon skip (ES) events had the highest accuracy, indicating its significant value in GBC prognosis. The constructed regulatory SF-AS network may explain the potential regulatory mechanism between SF and AS, which may be the mechanism through which AS events contribute to GBC survival outcomes. The findings confirm that AS events have a significant prognostic value in GBC, and we found a few effective prognostic signatures. We also hypothesized the mechanism underlying AS in GBC and discovered a potential regulatory mechanism between SF and AS.

SUBMITTER: Li X

PROVIDER: S-EPMC7074345 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer.

Li Xin X Wang Yaxuan Y Li Bingjie B Ma Wang W

Genes 20200216 2

Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic value of AS in GBC and the regulatory network of AS in GBC, which may highlight the mechanism through which AS contributes to GBC. In the present study, we obtained splicing event information (SpliceSeq) and c ...[more]

PMID: 32079071

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Project description:BackgroundIncreasing evidence indicated a close relationship between aberrant splicing variants and carcinoma, whereas comprehensive analysis of prognostic alternative splicing (AS) profiling in breast cancer (BRCA) is lacking and largely unknown.MethodsRNA-seq data and corresponding clinical information of BRCA patients were obtained and integrated from The Cancer Genome Atlas (TCGA). Then SpliceSeq software was used to assess seven AS types and calculate the Percent Spliced In (PSI) value. Univariate followed by stepwise multivariate Cox regression analyses identified survival associated AS events and constructed the AS signature, which were further sent for enrichment analysis, respectively. Besides, the splicing correlation network was constructed. Additionally, nomogram incorporating AS signature and clinicopathological characteristics was developed and its efficacy was evaluated with respect to discrimination, calibration and clinical utility.ResultsA total of 45,421 AS events were detected, among which 3071 events were found associated with overall survival (OS) after strict filtering. Parent genes of these prognostic events were involved in BRCA-related processes including NF-kappaB and HIF-1 signaling pathway. Besides, the final prognostic signature built with 20 AS events performed well with an area under the curve (AUC) of receiver operating characteristic (ROC) curve up to 0.957 for 5 years. And gene set enrichment analysis (GSEA) also confirmed the candidate 20 AS events contributed to progression of BRCA. Moreover, the nomogram that incorporated 20-AS-event-based classifier, age, pathological stage and Her-2 status showed good calibration and moderate discrimination, with C-index of 0.883 (95% CI, 0.844-0.921). Decision curve analysis (DCA) confirmed more benefit was added to survival prediction with our nomogram, especially in 5 or 8 years with threshold probability up to 80%. Finally, splicing correlation network revealed an obvious regulatory pattern of prognostic splicing factors (SF) in BRCA.ConclusionThis study provided a systematic portrait of survival-associated AS events involved in BRCA and further presented a AS-clinicopathological nomogram, which could be conveniently used to assist the individualized prediction of long-term survival probability for BRCA patients. And a series of bioinformatic analysis provided a promising perspective for further uncovering the underlying mechanisms of AS events and validating therapeutic targets for BRCA.

Dataset Information

Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer.

Publications

Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer.

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