The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma

Our plain-English summary of The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma, by L.T. Gold, S.E. Bray, N.M. Kernohan, et al (BJC Reports, 2023).

The study

• Authors: L.T. Gold, S.E. Bray, N.M. Kernohan, N. Henderson, M. Nowicki, G.R. Masson
• Journal: BJC Reports
• Published: 2023;1(1):4
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is a tumour that is strongly associated with a history of asbestos exposure, and which derives from mesothelial cells that line the serous cavities of the body. The tumour most commonly arises in the pleural cavity, but can also arise in the pericardium, peritoneum, and tunica vaginalis. At present the lesion has a very poor prognosis and is an incurable form of cancer with median survival times of up to 19 months being quoted for some histological subtypes. A large proportion of mesotheliomas have been shown to be arginine auxotrophic, leading to new research for therapeutics which might exploit this potential vulnerability.

Methods: We measured the levels of General Control Non-derepressible 2 (GCN2) protein in malignant mesothelioma tumour samples and determined whether these levels correlate with clinical outcomes.

Results: We observed that the expression levels of GCN2 correlated with patient survival and was an independent prognostic variable in pairwise comparisons with all available clinical data.

Conclusion: These findings suggest that GCN2 levels provides prognostic information and may allow for stratification of care pathways. It may suggest that targeting GCN2 is a viable strategy for mesothelioma therapy development.

© 2023. The Author(s).

In plain English

This laboratory study asked whether the amount of a protein called GCN2 in tumours was linked to survival in malignant pleural mesothelioma. The authors stained archived tumour samples on tissue microarrays from the UK Mesobank tissue bank. The arrays represented 204 patients, but three were excluded because no tissue sections were present for them. They scored GCN2 on a 0-to-500 scale and compared the scores with survival from diagnosis to death. Asbestos exposure was not examined. GCN2 scores were significantly associated with survival (p = 0.0009). Patients in the top two-fifths of GCN2 scores had a median survival of 181.5 days, against 461.5 days for the bottom two-fifths. GCN2 remained a significant predictor of survival when tumour subtype was taken into account, but not when cancer spread (metastasis) was taken into account (p = 0.4643). No statistically significant differences in GCN2 scores were detected between tumour subtypes. The authors concluded that GCN2 levels are a useful prognostic marker for survival, and suggested GCN2 might be a target for future treatments. They noted they did not know whether the GCN2 measured was active.

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 study of archived tumour tissue (tissue microarrays) stained for GCN2 protein, with scores compared against patient survival
• Who was studied: Tissue microarrays of malignant pleural mesothelioma tumour samples representing 204 patients, obtained from Mesobank (NHS Royal Papworth Hospital, UK). Three patients were excluded because no tissue sections were present for them. 90.2% were male and the median age was 69. Clinical data were complete to January 2022.
• Exposure: Not asbestos. The factor studied was the level of GCN2 protein in tumour tissue. It was scored as staining intensity (0 to 5) multiplied by the percentage of cells stained, giving 0 to 500. Asbestos exposure was not among the data analysed.
• Main results:
  • Three patients were excluded because no tissue sections were present for them in the slide set
  • GCN2 scores were significantly associated with survival (p = 0.0009)
  • Median survival was 181.5 days for patients in the upper two quintiles of GCN2 score, 461.5 days for those in the lower two quintiles, and 382.0 days for the rest of the cohort
  • In multivariate (Cox regression) analysis, GCN2 was a significant indicator of survival independent of histological subtype
  • GCN2 score was not a significant predictor of survival independent of metastasis score (p = 0.4643)
  • For predicting 1-year survival, GCN2 score had a C-statistic of 0.690. Adding GCN2 score to histopathology did not significantly improve the C-statistic.
  • The authors reported no correlation between GCN2 staining and histological subtype, metastasis score or tumour score; the figure marks these comparisons as not statistically significant
  • In univariate analysis, histological subtype (p less than 0.0001) and metastasis score (p = 0.0049) were linked to survival; tumour and node scores were not
• The authors' conclusion: The authors concluded that GCN2 levels are a useful prognostic biomarker for survival in malignant pleural mesothelioma, and suggested that targeting GCN2 with drugs may be worth exploring for future treatment
• Limitations the authors state:
  • The authors did not know the activation status of the GCN2 they measured

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Malignant Mesothelioma, Asbestos Exposure, Mesothelial Cells, Serous Cavities, Pleural Cavity, Pericardium, Peritoneum.

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