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

doi:10.1186/s13073-022-01060-8

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

Genome Med. 2022 May 30;14(1):58. doi: 10.1186/s13073-022-01060-8.

Authors

Jenette Creaney^#^{1

2

3}, Ann-Marie Patch^#^{4

5}, Venkateswar Addala^#^{4

5}, Sophie A Sneddon¹, Katia Nones⁴, Ian M Dick^{1

3}, Y C Gary Lee^{1

2

3}, Felicity Newell⁴, Ebony J Rouse^{1

3}, Marjan M Naeini⁴, Olga Kondrashova⁴, Vanessa Lakis⁴, Apostolos Nakas⁶, David Waller⁶, Annabel Sharkey⁶, Pamela Mukhopadhyay⁴, Stephen H Kazakoff⁴, Lambros T Koufariotis⁴, Aimee L Davidson^{4

5}, Priya Ramarao-Milne⁴, Oliver Holmes⁴, Qinying Xu⁴, Conrad Leonard⁴, Scott Wood⁴, Sean M Grimmond⁷, Raphael Bueno⁸, Dean A Fennell⁶, John V Pearson⁴, Bruce W Robinson^#^{9

10

11}, Nicola Waddell^#¹²

Affiliations

¹ 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.
² Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
³ Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.
⁴ Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
⁵ Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
⁶ Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.
⁷ University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.
⁸ Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁹ 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. [email protected].
¹⁰ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. [email protected].
¹¹ Centre for Respiratory Health, University of Western Australia, Nedlands, WA, Australia. [email protected].
¹² Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia. [email protected].

^# Contributed equally.

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: Immunotherapy; Malignant pleural mesothelioma; Mutational signatures; RNA sequencing; Tumour micro-environment; Whole genome sequencing.

Publication types

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

MeSH terms

Genomics
Humans
Lung Neoplasms* / genetics
Mesothelioma* / genetics
Mesothelioma, Malignant*
Pleural Neoplasms* / genetics
Pleural Neoplasms* / pathology
Tumor Microenvironment / genetics