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Genetics and Genomics

A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma

Abstract

Background

Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups.

Methods

We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM.

Results

The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction.

Conclusions

By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.

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Fig. 1: Schematic diagram of our study.
Fig. 2: Gene signature scores were able to classify mutation status.
Fig. 3: NF2 score was significantly associated with poor patient prognosis.
Fig. 4: Prognostic significance of BAP1, SETD2 and TP53 scores.
Fig. 5: Immune infiltration in the Bueno cohort was associated with patient prognosis.
Fig. 6: Establishment and validation of the prognostic prediction models.

Data availability

All datasets were previously published. The Methods section details how the data can be accessed.

Code availability

The code used in this study is available from the corresponding author upon request.

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Acknowledgements

We thank the Cheng Lab members for helpful discussions and suggestions.

Funding

This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) (RR180061 to CC, RR170048 to CA, RP200443 to HL) and the National Cancer Institute of the National Institutes of Health (1R37CA248478-01A1 to BB). CC and CA are CPRIT Scholars in Cancer Research.

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CC and CA designed and supervised the study. TN and CC performed data analyses and interpreted the results. TN, CC, CA, HL and BB contributed to writing the manuscript.

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Correspondence to Chao Cheng.

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Nguyen, T.T., Lee, HS., Burt, B.M. et al. A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma. Br J Cancer 127, 1691–1700 (2022). https://doi.org/10.1038/s41416-022-01950-z

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