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

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-MilneOliver Holmes, Qinying Xu, Conrad Leonard, Scott Wood, Sean M. Grimmond, Raphael Bueno, Dean A. Fennell, John V. Pearson, Bruce W. Robinson, Nicola Waddell

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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.

Original language	English
Article number	58
Journal	Genome Medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13073-022-01060-8
Publication status	Published - Dec 2022

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Creaney, J., Patch, A. M., Addala, V., Sneddon, S. A., Nones, K., Dick, I. M., Lee, Y. C. G., Newell, F., Rouse, E. J., Naeini, M. M., Kondrashova, O., Lakis, V., Nakas, A., Waller, D., Sharkey, A., Mukhopadhyay, P., Kazakoff, S. H., Koufariotis, L. T., Davidson, A. L., ... Waddell, N. (2022). Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma. Genome Medicine, 14(1), Article 58. https://doi.org/10.1186/s13073-022-01060-8

@article{3007b69ebcd142e3a60dd203e85ad8a9,

title = "Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma",

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 {\textquoteleft}hot{\textquoteright} 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",

author = "Jenette Creaney and Patch, {Ann Marie} and Venkateswar Addala and Sneddon, {Sophie A.} and Katia Nones and Dick, {Ian M.} and Lee, {Y. C.Gary} and Felicity Newell and Rouse, {Ebony J.} and Naeini, {Marjan M.} and Olga Kondrashova and Vanessa Lakis and Apostolos Nakas and David Waller and Annabel Sharkey and Pamela Mukhopadhyay and Kazakoff, {Stephen H.} and Koufariotis, {Lambros T.} and Davidson, {Aimee L.} and Priya Ramarao-Milne and Oliver Holmes and Qinying Xu and Conrad Leonard and Scott Wood and Grimmond, {Sean M.} and Raphael Bueno and Fennell, {Dean A.} and Pearson, {John V.} and Robinson, {Bruce W.} and Nicola Waddell",

note = "Funding Information: This work was funded by the Australian National Medical and Research Council (NHMRC) (APP1089404). NW is funded by a National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (APP1139071). BWR is funded by an NHMRC Practitioner Fellowship (APP1108638). VA and ALD are supported by Australian Government Research Training Program (RTP) Scholarships and QIMR Berghofer HDC PhD top up Scholarships. This work and this research was performed on QIMR Berghofer computing infrastructure supported by The Ian Potter Foundation and The John Thomas Wilson Endowment. We are grateful to the Estate of Mr Stewart Coggins for support to AMP, PM and SHK. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13073-022-01060-8",

language = "English",

volume = "14",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

number = "1",

}

Creaney, J, Patch, AM, Addala, V, Sneddon, SA, Nones, K, Dick, IM , Lee, YCG, Newell, F, Rouse, EJ, Naeini, MM, Kondrashova, O, Lakis, V, Nakas, A, Waller, D, Sharkey, A, Mukhopadhyay, P, Kazakoff, SH, Koufariotis, LT, Davidson, AL, Ramarao-Milne, P, Holmes, O, Xu, Q, Leonard, C, Wood, S, Grimmond, SM, Bueno, R, Fennell, DA, Pearson, JV, Robinson, BW & Waddell, N 2022, 'Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma', Genome Medicine, vol. 14, no. 1, 58. https://doi.org/10.1186/s13073-022-01060-8

TY - JOUR

T1 - Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma

AU - Creaney, Jenette

AU - Patch, Ann Marie

AU - Addala, Venkateswar

AU - Sneddon, Sophie A.

AU - Nones, Katia

AU - Dick, Ian M.

AU - Lee, Y. C.Gary

AU - Newell, Felicity

AU - Rouse, Ebony J.

AU - Naeini, Marjan M.

AU - Kondrashova, Olga

AU - Lakis, Vanessa

AU - Nakas, Apostolos

AU - Waller, David

AU - Sharkey, Annabel

AU - Mukhopadhyay, Pamela

AU - Kazakoff, Stephen H.

AU - Koufariotis, Lambros T.

AU - Davidson, Aimee L.

AU - Ramarao-Milne, Priya

AU - Holmes, Oliver

AU - Xu, Qinying

AU - Leonard, Conrad

AU - Wood, Scott

AU - Grimmond, Sean M.

AU - Bueno, Raphael

AU - Fennell, Dean A.

AU - Pearson, John V.

AU - Robinson, Bruce W.

AU - Waddell, Nicola

N1 - Funding Information: This work was funded by the Australian National Medical and Research Council (NHMRC) (APP1089404). NW is funded by a National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (APP1139071). BWR is funded by an NHMRC Practitioner Fellowship (APP1108638). VA and ALD are supported by Australian Government Research Training Program (RTP) Scholarships and QIMR Berghofer HDC PhD top up Scholarships. This work and this research was performed on QIMR Berghofer computing infrastructure supported by The Ian Potter Foundation and The John Thomas Wilson Endowment. We are grateful to the Estate of Mr Stewart Coggins for support to AMP, PM and SHK. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Immunotherapy

KW - Malignant pleural mesothelioma

KW - Mutational signatures

KW - RNA sequencing

KW - Tumour micro-environment

KW - Whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85130995249&partnerID=8YFLogxK

U2 - 10.1186/s13073-022-01060-8

DO - 10.1186/s13073-022-01060-8

M3 - Article

C2 - 35637530

AN - SCOPUS:85130995249

SN - 1756-994X

VL - 14

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 58

ER -

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

Abstract

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Practitioner Fellowship - Robinson

Characterising the Mutations Signatures Potential New Therapeutic Targets & Biomarkers in Malignant Mesothelioma using Whole Genome Analysis

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

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Practitioner Fellowship - Robinson

Characterising the Mutations Signatures Potential New Therapeutic Targets & Biomarkers in Malignant Mesothelioma using Whole Genome Analysis

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