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. 2020 Apr 13;12(7):5878-5893.
doi: 10.18632/aging.102983. Epub 2020 Apr 13.

Survival-associated Alternative Splicing Signatures in Non-Small Cell Lung Cancer

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Free PMC article

Survival-associated Alternative Splicing Signatures in Non-Small Cell Lung Cancer

Deze Zhao et al. Aging (Albany NY). .
Free PMC article

Abstract

Alternative splicing (AS) is fundamental to transcriptome and proteome richness, and data from recent studies suggested a critical association between AS and oncogenic processes. To date, no systematic analysis has been conducted on AS from the perspective of different sexes and subtypes in non-small-cell lung cancer (NSCLC). Thus, we integrated the information of NSCLC patients from The Cancer Genome Atlas (TCGA) and evaluated AS profiles from the perspectives of sex and subtype. Eventually, a total of 813 and 1020 AS events were found to be significantly related to the overall survival (OS) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. Four prognostic prediction models performed well at 1, 3, and 5 years, with an area under the receiver operating characteristic (ROC) curve (AUC) greater than 0.75. Notably, we explored the upstream splicing factors (SFs) and downstream regulatory mechanisms of the OS-associated AS events and verified four differentially expressed alternative splicing (DEAS) events via qPCR. These findings can provide important guidance for subsequent studies. In addition, we also constructed nomograms to facilitate early screening by clinicians and to determine patient outcomes in NSCLC.

Keywords: LUAD; LUSC; TCGA; alternative splicing (AS).

Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart for profiling AS of NSCLC. TCGA, The Cancer Genome Atlas; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; DEAS, differentially expressed alternative splicing; SF, splicing factor; KM, Kaplan Meier.
Figure 2
Figure 2
Overview of DEAS events profiling in NSCLC cohorts. (A) Schematic diagram of seven splicing pattern. (B) Seven types of AS events and corresponding parents’ genes. The gray bars represent the prognosis irrelevant AS events and related genes. The color bars represent the DEAS events and parent genes. (CE) The Venn diagram compares DEAS in the four cohorts. (F) UpSet plot of intersections and aggregates among different types of DEAS events in NSCLC. One gene could have more than one type of OS-associated AS event.
Figure 3
Figure 3
Functional analyses on parent genes from OS-associated DEAS events in NCSLC, including GO and KEGG. (A) LUAD_MALE group, (B) LUAD_FEMALE group, (C) LUSC_MALE group, (D) LUSC_FEMALE group.
Figure 4
Figure 4
Determination and analysis of the final prognostic models in four cohorts. (A) LUAD_MALE group, (B) LUAD_FEMALE group, (C) LUSC_MALE group, (D) LUSC_FEMALE group. Patients were divided into high- and low-risk subgroups based on the median cut of risk score calculated separately. The upper part of each assembly indicates distribution of patients’ survival status and survival times ranked by risk score, the middle part represents the risk score curve, and the bottom heatmap displays splicing pattern of the AS from final prognostic models. Color transition from blue to red indicates the increasing PSI score of corresponding AS event from low to high.
Figure 5
Figure 5
The prognostic analysis of DEAS events in NSCLC. (A) LUAD_MALE group, (B) LUAD_FEMALE group, (C) LUSC_MALE group, (D) LUSC_FEMALE group. The left plot is the K-M plot of prognostic models constructed with OS-related DEAS events for NSCLC patients. The right plot is ROC curves with calculated AUCs of prognostic models constructed with OS-related DEAS events.
Figure 6
Figure 6
The AS-clinicopathologic nomogram for prediction on survival probability in patients with NSCLC. (AD) Development of AS-clinicopathologic nomogram for predicting 1-, 3-, and 5-years OS for LUAD_MALE group, LUAD_FEMALE group, LUSC_MALE group, and LUSC_FEMALE group, with the final AS signature and independent prognostic factors. (EH) Calibration plot of the AS-clinicopathologic nomogram in terms of agreement between nomogram-predicted and observed 1-, 3-, and 5-years outcomes in four cohorts. The actual performances of our model are shown by green, blue, and red lines. And the silver line of 45° represents the ideal performance.
Figure 7
Figure 7
The correlation network of DESF and OS-related DEAS. (A) LUAD_MALE group, (B) LUAD_FEMALE group, (C) LUSC_MALE group, (D) LUSC_FEMALE group. The size indicates the degree of the point in the network, and the intensity of the color indicates the strength of its characteristics. For DESFs, the peripheral red dots indicate upregulation (log fold change (FC) > 1), while the blue dots indicate downregulation (logFC < 1). For DEAS events, the central red dots indicate poor prognosis (hazard ratio (HR) > 1), while the blue dots indicate better clinical outcomes (HR < 1).
Figure 8
Figure 8
OS-related DEAS events expression in NSCLC. (A) The top plot demonstrated the splicing pattern of AT〇HNRNPLL〇ID〇053259. The bottom plot displays the PSI of AT〇HNRNPLL in cancer and normal tissues. (B) The top plot demonstrated the splicing pattern of ES〇HPCAL1〇ID〇052659. The bottom plot displays the PSI of ES〇HPCAL1 in cancer and normal tissues. (C) The top plot demonstrated the splicing pattern of RI〇CCDC88A〇ID〇053613. The bottom plot displays the PSI of RI〇CCDC88A in cancer and normal tissues. (D) The top plot demonstrated the splicing pattern of RI〇RPL29〇ID〇065167. The bottom plot displays the PSI of RI〇RPL29 in cancer and normal tissues. In the schematic diagram, green lines represent transcripts before splicing and the red lines represent transcripts after splicing.

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