학술논문
Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.
Document Type
Academic Journal
Author
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.; 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.; 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.; 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.; Nones K; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; 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.; 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.; Newell F; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; 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.; Naeini MM; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Kondrashova O; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Lakis V; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Nakas A; Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.; Waller D; Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.; Sharkey A; Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.; Mukhopadhyay P; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Kazakoff SH; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Koufariotis LT; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; 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.; Ramarao-Milne P; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Holmes O; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Xu Q; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Leonard C; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Wood S; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; Grimmond SM; University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.; Bueno R; Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA, USA.; Fennell DA; Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.; Pearson JV; Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.; 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.; 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.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE
Subject
Language
English
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).)
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).)