Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma

Our plain-English summary of Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma, by Y. Lin, B.M. Burt, H.S. Lee, et al (NPJ Precision Oncology, 2024).

The study

• Authors: Y. Lin, B.M. Burt, H.S. Lee, T.T. Nguyen, H.J. Jang, C. Lee, W. Hong, R.T. Ripley, C.I. Amos, C. Cheng
• Journal: NPJ Precision Oncology
• Published: 2024;8(1):47
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

© 2024. The Author(s).

In plain English

This study built and tested a gene-expression score, called PRACME, intended to sort patients with malignant pleural mesothelioma (MPM) by expected survival. The authors sequenced RNA from 78 samples taken from three regions of the tumors of 26 MPM patients who had surgery from 2017 to 2019. They used these with public mesothelioma data (87 samples) to select 29 genes. In two separate MPM datasets (Bueno and Bott), higher scores were associated with poorer survival. In the Bueno data the score still added prognostic information after adjusting for age, sex, stage, histology and asbestos exposure. Sarcomatoid tumors had the highest median score. The article states that scores were significantly higher in the asbestos-exposed group, and that patients had longer survival than those not exposed. The score was associated with time to relapse in one lung adenocarcinoma dataset (Okayama), with similar results in another (Shedden), but was not informative in lung squamous cell carcinoma. A lung cancer score (ORACLE) also predicted MPM survival. The authors concluded PRACME provided prognostic stratification in MPM. They noted that their MPM data were smaller than the data behind ORACLE.

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: Laboratory and statistical study that developed a prognostic gene-expression signature from multi-region tumor RNA sequencing and public data, then tested it in independent mesothelioma and lung cancer datasets
• Who was studied: 26 patients with malignant pleural mesothelioma treated at Baylor College of Medicine (Houston) who underwent surgery (extrapleural pneumonectomy or extended pleurectomy/decortication) from 2017 to 2019, with 78 tumor samples (superior, lateral and inferior regions). The median age was 68.5 years (range 39 to 80); 18 were male and 8 female; 17 had epithelioid and 9 biphasic histology. Public datasets were also used: TCGA-MESO (87 samples), Bueno MPM (211 samples), Bott MPM (53 samples), lung adenocarcinoma datasets from Okayama (226), Shedden (442) and Lee (63), and 249 lung squamous cell carcinoma patients.
• Exposure: The study measured tumor gene expression, not asbestos dose. In the 26-patient cohort, asbestos exposure history was available for 21 patients, and 13 (62%) had a history of exposure. Asbestos exposure (yes or no) was one of the adjustment variables in the Bueno dataset analysis. No fiber types, products or jobs are given.
• Main results:
  • In the Bueno MPM dataset, the PRACME score was significantly associated with survival from surgery in univariable analysis (hazard ratio greater than 1, p = 3e-06)
  • In the Bueno MPM dataset, the PRACME score provided additional prognostic value after adjusting for age, sex, stage, histology and asbestos exposure
  • The prognostic value of PRACME was also confirmed in the Bott MPM dataset
  • Among histological subtypes, sarcomatoid samples had the highest median PRACME score, which corresponded to the poorest prognosis
  • When patients were grouped by asbestos exposure, the PRACME score was significantly higher in the exposed group. The article states that patients had longer survival than those who were not exposed.
  • MPM samples with higher PRACME scores tended to have lower immune cell infiltration (Bueno and TCGA-MESO datasets)
  • The lung cancer signature ORACLE was also informative in MPM patients in the TCGA-MESO, Bueno and Bott datasets
  • In the Okayama lung adenocarcinoma data, the PRACME score was associated with time to relapse (hazard ratio greater than 1, p = 6e-04). Similar results were reported in the Shedden lung adenocarcinoma dataset, for which the outcome is not specified in the text.
  • In lung squamous cell carcinoma patients, PRACME was not informative of prognosis
  • PRACME and ORACLE scores were correlated: R = 0.62 in the Bueno MPM data and R = 0.68 in the Okayama lung adenocarcinoma data
  • Of 948 MPM and 472 lung adenocarcinoma genes with high between-tumor and low within-tumor variation (Q4 genes), 208 were shared
  • Gene amplification profiles of MPM and lung adenocarcinoma (TCGA data) were more strongly correlated (R = 0.77) than gene deletion profiles (R = 0.43)
• The authors' conclusion: The authors concluded that the PRACME clonal signature provided prognostic stratification in MPM. They also concluded that the study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.
• Limitations the authors state:
  • The multi-region and TCGA data used to build PRACME were smaller than those used for the lung cancer signature ORACLE, which the authors suggest may explain why ORACLE predicted MPM prognosis slightly better
  • Sampling three regions (superior, lateral, inferior) differs from the TRACERx approach, which might estimate within-tumor variation more effectively
  • Further research is needed to know which cancer types share prognostic signatures and how far cross-cancer prediction extends

Topics

Medical terms in this study, explained in our Lexicon: Prognosis, Mesothelioma, Lung Adenocarcinoma, Pleural Mesothelioma, Biomarker.

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