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

Genomics Humans Lung Neoplasms / genetics Mesothelioma / genetics Mesothelioma, Malignant Pleural Neoplasms / genetics Tumor Microenvironment / genetics
Immunotherapy Malignant pleural mesothelioma Mutational signatures RNA sequencing Tumour micro-environment Whole genome sequencing

Journal

Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844

Informations de publication

Date de publication:
30 05 2022
Historique:
received: 18 08 2021
accepted: 15 05 2022
entrez: 31 5 2022
pubmed: 1 6 2022
medline: 3 6 2022
Statut: epublish

Résumé

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

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13073-022-01060-8 PMID: 35637530 PMC: PMC9150319
pubmed: 35637530
doi: 10.1186/s13073-022-01060-8
pii: 10.1186/s13073-022-01060-8
pmc: PMC9150319
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

58

Informations de copyright

© 2022. The Author(s).

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Auteurs

Jenette Creaney (J)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.

Ann-Marie Patch (AM)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Venkateswar Addala (V)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Sophie A Sneddon (SA)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.

Katia Nones (K)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Ian M Dick (IM)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.
Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.

Y C Gary Lee (YCG)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.

Felicity Newell (F)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Ebony J Rouse (EJ)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.
Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.

Marjan M Naeini (MM)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Olga Kondrashova (O)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Vanessa Lakis (V)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Apostolos Nakas (A)

Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.

David Waller (D)

Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.

Annabel Sharkey (A)

Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.

Pamela Mukhopadhyay (P)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Stephen H Kazakoff (SH)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Lambros T Koufariotis (LT)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Aimee L Davidson (AL)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Priya Ramarao-Milne (P)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Oliver Holmes (O)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Qinying Xu (Q)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Conrad Leonard (C)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Scott Wood (S)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Sean M Grimmond (SM)

University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Raphael Bueno (R)

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA, USA.

Dean A Fennell (DA)

Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.

John V Pearson (JV)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Bruce W Robinson (BW)

National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia. bruce.robinson@uwa.edu.au.
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. bruce.robinson@uwa.edu.au.
Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia. bruce.robinson@uwa.edu.au.
ORCID: 0000-0001-7865-2760

Nicola Waddell (N)

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia. nic.waddell@qimrberghofer.edu.au.
ORCID: 0000-0002-3950-2476

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Classifications MeSH

questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Tumeurs mésotheliales › Mésothéliome › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs de la plèvre › Mésothéliome malin › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs de la plèvre › Comprehensive genomic and tumour immune...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Comprehensive genomic and tumour immune...