Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma

Our plain-English summary of Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma, by J. Lai, H. Yang, T. Xu (BMC Cancer, 2021).

The study

• Authors: J. Lai, H. Yang, T. Xu
• Journal: BMC Cancer
• Published: 2021;21(1):848
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM.

Methods: We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan-Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs).

Results: A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM.

Conclusion: Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.

© 2021. The Author(s).

In plain English

This was a computer-based (bioinformatics) analysis of public tumor data, not a study of asbestos exposure. The authors studied alternative splicing, the way one gene can produce different versions of its message, in malignant mesothelioma samples from The Cancer Genome Atlas (TCGA). Of 87 patients, 4 with less than 30 days of follow-up were excluded. The authors detected 43,433 splicing events and found 3976 linked to overall survival, with exon-skipping events the most common type. Risk scores built from these events predicted survival with AUC values above 0.9. A score built from key events reached 0.941 at 3 years and 0.997 at 5 years, and the authors reported it as an independent prognostic factor. The score was significantly lower in the epithelioid subtype. Asbestos exposure was one of the clinical variables in the analysis, but no separate asbestos result was reported. The abstract and the results section contradict each other on which risk group had more of several immune cell types. The authors concluded the signature may serve as an effective risk model. They noted the results were not confirmed by experiments and the sample size was limited.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics (computational) analysis of publicly available tumor sequencing and clinical data
• Who was studied: Primary malignant mesothelioma specimens from The Cancer Genome Atlas (TCGA): 87 patients were included and 4 with less than 30 days of follow-up were excluded, leaving 83. Data were accessed in 2021.
• Exposure: The factor studied was alternative splicing events in tumor tissue, not asbestos. Asbestos exposure was one of the clinical variables in the survival analyses, recorded as a yes/no variable. No fiber types or doses were given, and no separate asbestos result was reported.
• Main results:
  • Across the mesothelioma samples, 43,433 alternative splicing events were detected in 10,145 parent genes.
  • 3976 splicing events, involving 2532 parent genes, were associated with overall survival. Exon-skipping events made up the greatest proportion, with 1363 survival-related exon-skipping events in 1069 genes.
  • Prognostic signatures built for each of the seven splicing types all had AUC values greater than 0.9 at 3 and 5 years.
  • The risk score built from key splicing events across all types had AUC values of 0.941 for 3-year survival and 0.997 for 5-year survival.
  • The authors reported that this risk score was an independent prognostic factor.
  • The risk score was significantly lower in patients with the epithelioid subtype.
  • The risk score had no significant correlation with age, sex, T stage, N stage, M stage or clinical stage.
  • In unsupervised clustering, most patients with high immune infiltration belonged to the high-risk group.
  • The results section states that cytotoxic T cells, NK cells and Th17 cells were higher in the low-risk group, and iTreg cells were lower in the low-risk group. The abstract states the reverse, placing these differences in the high-risk group.
  • 13 of 119 splicing factors were associated with overall survival. Three of them (HSPB1, INTS1 and LUC7L2) were reported to predict survival.
• The authors' conclusion: The authors concluded that prognostic signatures based on key splicing events may serve as an effective risk model to predict survival in malignant mesothelioma. In the abstract, they also described the signature as a better marker than the TNM staging system.
• Limitations the authors state:
  • The study relied on bioinformatics methods only, and the results were not confirmed by experiments.
  • The sample size was limited, and the prognostic model still needs further internal and external validation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Prognosis, Mesothelioma, Overall Survival, Epithelioid, TNM Staging.

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