Genome Medicine (May 2022)
Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma
- Jenette Creaney,
- Ann-Marie Patch,
- Venkateswar Addala,
- Sophie A. Sneddon,
- Katia Nones,
- Ian M. Dick,
- Y. C. Gary Lee,
- Felicity Newell,
- Ebony J. Rouse,
- Marjan M. Naeini,
- Olga Kondrashova,
- Vanessa Lakis,
- Apostolos Nakas,
- David Waller,
- Annabel Sharkey,
- Pamela Mukhopadhyay,
- Stephen H. Kazakoff,
- Lambros T. Koufariotis,
- Aimee L. Davidson,
- Priya Ramarao-Milne,
- Oliver Holmes,
- Qinying Xu,
- Conrad Leonard,
- Scott Wood,
- Sean M. Grimmond,
- Raphael Bueno,
- Dean A. Fennell,
- John V. Pearson,
- Bruce W. Robinson,
- Nicola Waddell
Affiliations
- Jenette Creaney
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Ann-Marie Patch
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Venkateswar Addala
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Sophie A. Sneddon
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Katia Nones
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Ian M. Dick
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Y. C. Gary Lee
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Felicity Newell
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Ebony J. Rouse
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Marjan M. Naeini
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Olga Kondrashova
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Vanessa Lakis
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Apostolos Nakas
- Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust
- David Waller
- Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust
- Annabel Sharkey
- Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust
- Pamela Mukhopadhyay
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Stephen H. Kazakoff
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Lambros T. Koufariotis
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Aimee L. Davidson
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Priya Ramarao-Milne
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Oliver Holmes
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Qinying Xu
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Conrad Leonard
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Scott Wood
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Sean M. Grimmond
- University of Melbourne Centre for Cancer Research, University of Melbourne
- Raphael Bueno
- Division of Thoracic Surgery, Brigham and Women’s Hospital
- Dean A. Fennell
- Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust
- John V. Pearson
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- Bruce W. Robinson
- National Centre for Asbestos Related Disease, Medical School, University of Western Australia
- Nicola Waddell
- Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute
- DOI
- https://doi.org/10.1186/s13073-022-01060-8
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
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.
Keywords
- Malignant pleural mesothelioma
- Whole genome sequencing
- RNA sequencing
- Mutational signatures
- Tumour micro-environment
- Immunotherapy
