Identification of prognostic and bone metastasis​-related alternative splicing signatures in mesothelioma

Our plain-English summary of Identification of prognostic and bone metastasis​-related alternative splicing signatures in mesothelioma, by R. Huang, Z. Zheng, S. Liu, et al (Cancer Medicine, 2021).

The study

• Authors: R. Huang, Z. Zheng, S. Liu, P. Yan, D. Song, H. Yin, P. Hu, X. Zhu, Z. Chang, Y. Liu, J. Zhuang, T. Meng, Z. Huang, J. Zhang
• Journal: Cancer Medicine
• Published: 2021;10(13):4478-4492
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma (MESO) is an infrequent tumor derived from mesothelial cells of pleura, peritoneum, pericardium, and tunica vaginalis testis. Despite advancement in technologies and better understanding of tumor progression mechanism, the prognosis of MESO remains poor. The role of alternative splicing events (ASEs) in the oncogenesis, tumor metastasis and drug resistance has been widely discussed in multiple cancers. But the prognosis and potential therapeutic value of ASEs in MESO were not clearly studied by now. We constructed a prognostic model using RNA sequencing data and matched ASE data of MESO patients obtained from the TCGA and TCGASpliceSeq database. A total of 3,993 ASEs were identified associated with overall survival using Cox regression analysis. Eight of them were finally figured out to institute the model by lasso regression analysis. The risk score of the model can predict the prognosis independently. Among the identified 390 splicing factors (SF), HSPA1A and DDX3Y was significantly associated with 43 OS-SEs. Among these OS-SEs, SNX5-58744-AT (p = 0.048) and SNX5-58745-AT (p = 0.048) were significantly associated with bone metastasis. Co-expression analysis of signal pathways and SNX5-58744-AT, SNX5-58745-AT was also depicted using GSVA. Finally, we proposed that splicing factor (SF) HSPA1A could regulate SNX5-58744-AT (R = -0.414) and SNX5-58745-AT (R = 0.414) through the pathway "Class I MHC mediated antigen processing and presentation" (R = 0.400). In this way, tumorigenesis and bone metastasis of MESO were controlled.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This was a computer-based (bioinformatics) analysis of public genetic data, not a study of asbestos exposure. The authors used RNA sequencing and alternative splicing data for 84 mesothelioma patients from The Cancer Genome Atlas (TCGA). Of these, 25 had distant metastasis and 4 had bone metastasis. Alternative splicing lets one gene produce different protein versions. Of 28,694 splicing events found, 3,993 were associated with overall survival. The authors built a risk score from eight of these events. Its area under the ROC curve was 0.867, and in multivariate analysis its hazard ratio was 1.223 (95% CI 1.146 to 1.304). Two splicing events in the SNX5 gene were associated with bone metastasis (p = 0.048 each) and were linked by correlation to the splicing factor HSPA1A. The authors proposed that HSPA1A regulates these events through the "Class I MHC mediated antigen processing and presentation" pathway, affecting prognosis. They stated several limits. Their results rest on correlation analysis, which only shows mathematical probability. Laboratory experiments are needed to confirm the mechanism. The data sets used to build the prognostic model came from Western countries.

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 analysis of public RNA sequencing and alternative splicing databases (TCGA, TCGASpliceSeq), with survival modelling (Cox and lasso regression), correlation analysis, and checks against other online databases; no laboratory experiments
• Who was studied: 84 mesothelioma patients in the TCGA dataset: 69 male and 15 female. 25 had distant metastasis and 59 did not; 4 had bone metastasis. Stages: I 10, II 16, III 42, IV 16. The authors state that the data sets used to build the prognostic model came from Western countries. Dates are not given.
• Exposure: No asbestos or other environmental exposure was analyzed. The factor studied was alternative splicing events (ASEs) in tumor RNA, along with 390 splicing factors from the SpliceAid2 database.
• Main results:
  • In the 84-patient cohort, 28,694 alternative splicing events in 9,598 genes were identified.
  • 3,993 splicing events were associated with overall survival in univariate Cox regression.
  • The prognostic model built from eight splicing events had an area under the ROC curve of 0.867.
  • In univariate Cox analysis, the risk score had a hazard ratio of 1.211 (95% CI 1.141 to 1.285, p less than 0.001).
  • In multivariate Cox analysis adjusted for age, gender, pathological stage and TNM stage, the risk score had a hazard ratio of 1.223 (95% CI 1.146 to 1.304, p less than 0.001).
  • The splicing factors HSPA1A and DDX3Y were correlated with 43 survival-associated splicing events.
  • Two splicing events in the SNX5 gene, SNX5-58744-AT and SNX5-58745-AT, were associated with bone metastasis (p = 0.048 each). Only 4 of the 84 patients had bone metastasis.
  • The pathways most co-expressed with the two SNX5 splicing events were "Spliceosome" (R = 0.400, p less than 0.001), "Proteasome" (R = 0.390, p less than 0.001) and "Drug metabolism cytochrome P450" (R = 0.320, p less than 0.001).
  • In external databases, 9 genes were associated with survival and metastasis. CDC20 and SF3B4 were significant in all the external databases.
• The authors' conclusion: The authors proposed that the SNX5 splicing events SNX5-58744-AT and SNX5-58745-AT, regulated by the splicing factor HSPA1A, play a critical role in mesothelioma prognosis through the "Class I MHC mediated antigen processing and presentation" pathway.
• Limitations the authors state:
  • The mesothelioma data available in public datasets are restricted, which might cause error or bias.
  • The results rest on bioinformatics and correlation analysis, which only shows mathematical probability.
  • Molecular biology experiments are needed to confirm the proposed regulatory mechanism.
  • All data sets used to build the prognostic model came from Western countries. Caution is needed when applying the results to patients from Asian countries or to samples tested on other platforms.

Topics

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

Medical terms in this study, explained in our Lexicon: Metastasis, Mesothelioma, Mesothelial Cells, Pleura, Peritoneum, Pericardium, Tunica Vaginalis, Prognosis.

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