Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma

Our plain-English summary of Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma, by J. Creaney, A.M. Patch, V. Addala, et al (Genome Medicine, 2022).

The study

• Authors: J. Creaney, A.M. Patch, V. Addala, S.A. Sneddon, K. Nones, I.M. Dick, Y.C.G. Lee, F. Newell, E.J. Rouse, M.M. Naeini, O. Kondrashova, V. Lakis, A. Nakas, D. Waller, A. Sharkey, P. Mukhopadhyay, S.H. Kazakoff, L.T. Koufariotis, A.L. Davidson, P. Ramarao-Milne, O. Holmes, Q. Xu, C. Leonard, S. Wood, S.M. Grimmond, R. Bueno, D.A. Fennell, J.V. Pearson, B.W. Robinson, N. Waddell
• Journal: Genome Medicine
• Published: 2022;14(1):58
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials.

Methods: We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment.

Results: The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a 'hot' immune environment independent of the somatic mutations.

Conclusions: We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.

© 2022. The Author(s).

In plain English

This laboratory genetic study examined malignant pleural mesothelioma tumours. The authors sequenced the whole genomes of 58 tumour samples, taken from pleural tissue, pleural fluid and short-term cell lines. They then combined these with published data, giving 229 samples, to search for genes that drive the cancer. Of the 58 patients, 85% reported previous asbestos exposure. The article did not describe fiber types or doses. The tumours carried few mutations, an average of 1.36 per megabase. Whole genome duplication occurred in 17 of 58 cases and was associated with shorter overall survival. Two similar mutation patterns, SBS5 or SBS40, made up more than half of the mutations in 54 of 58 samples. These patterns were not associated with asbestos exposure. The authors only speculated that SBS40 might reflect inflammation from asbestos. The combined analysis identified 7 driver genes, including BAP1, NF2 and TP53. The most common immune cells were M2 macrophages, and low TGFB1 gene activity was associated with better survival. Fewer than 10% of samples showed an immune 'hot' pattern. The authors proposed that, depending on the immune environment, patients may respond to immune checkpoint or TGFB blockade.

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: Tumour genomic study: whole genome sequencing and RNA sequencing of mesothelioma samples, combined with previously published genomic data for a pooled analysis of driver genes
• Who was studied: 58 pathologically confirmed malignant pleural mesothelioma samples (21 pleural tissue, 29 pleural effusions, 8 low-passage effusion cell lines) from patients consenting at centres in Perth (Western Australia, 42 patients), Leicester (UK, 12) and Boston (USA, 4). Patients were 76% male (44/58) with an average age at diagnosis of 68 years. Data were pooled with TCGA (74 cases) and Bueno et al. samples, giving 229 for the driver-gene analysis.
• Exposure: Asbestos exposure was self-reported by 85% of the 58 sequenced patients; no fiber types, products, jobs or doses were described. Fifty percent were current or previous smokers. The study's focus was tumour genetics and immune features rather than exposure.
• Main results:
  • In the 58 sequenced tumours, average mutation burden was 1.36 mutations per megabase (median 1.31, range 0.24 to 2.24)
  • Whole genome duplication occurred in 29% (17 of 58) of cases and was significantly associated with decreased overall survival (p-value less than 0.01)
  • 54 of 58 samples contained SBS5 or SBS40 mutational signature at a proportion of more than 50%
  • The proportion of SBS40 or SBS5 signatures was not associated with asbestos exposure, smoking history or age at diagnosis
  • Only two of the 58 sequenced samples were considered homologous recombination (HR) deficient
  • The pooled analysis of 229 patients identified 7 driver genes: BAP1, NF2, TP53, SETD2, LATS2, DDX3X and SETDB1. A significantly mutated or candidate driver gene was found in 61.2% (140/229) of samples.
  • TERT promoter mutations were found in 3 of 58 samples (5.2%)
  • In the TCGA and Creaney et al. samples, the most prevalent immune cell type in the tumour environment was M2 macrophages
  • Low TGFB1 expression was associated with better survival in both the TCGA and Creaney et al. datasets (p less than 0.05, log rank test)
  • A small subset of samples (less than 10%) formed a group with higher cytolytic scores and high immune checkpoint receptor expression, an immune 'hot' pattern; BAP1 status was not associated with neoantigen load or this subgroup
  • Cytolytic activity was not associated with survival in MPM
• The authors' conclusion: The authors concluded that MPM is driven by mutations in tumour suppressor genes and frequently contains the SBS40 signature. They proposed that, depending on the immune microenvironment, patients may respond to immune checkpoint and/or TGFB blockade.
• Limitations the authors state:
  • Tumour cell enrichment of effusion samples (cell culture or CD45 depletion) affects the proportion of immune cells measured
  • The analysis of TERT promoter mutations was limited because only 3 samples had one
  • Other mechanisms of BAP1 inactivation, such as methylation, were not assessed
  • SBS5 and SBS40 are similar 'flat' signatures, so their relative assignment may be uncertain
  • The idea that SBS40 reflects inflammatory effects of asbestos exposure was offered only as speculation needing confirmation in more samples or functional studies

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Overall Survival, Clinical Trial, Somatic Mutation, Macrophage.

Related studies

• Development and Evaluation of Antibody Proteomics Technology for Rapid and Comprehensive Identification of Potential Biomarkers and Therapeutic Targets — K. Nagano (2018)
• An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma — A. Linton, Y.Y. Cheng, et al. (2014)
• Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing — A.M. Patch, K. Nones, et al. (2018)
• Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths — A. Nash, J. Creaney (2023)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers — J. Creaney, I.M. Dick, et al. (2016)

Browse return to medical research.