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Pan-cancer deconvolution of tumour composition using DNA methylation

Pan-cancer deconvolution of tumour composition using DNA methylation
Pan-cancer deconvolution of tumour composition using DNA methylation
The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: ‘immune hot’ and ‘immune cold’, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.
1-13
Chakravarthy, Ankur
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Furness, Andrew
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Joshi, Kroopa
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Ghorani, Ehsan
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Ford, Kirsty
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Ward, Matthew J.
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King, Emma V.
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Lechner, Matt
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Marafioti, Teresa
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Quezada, Sergio A.
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Thomas, Gareth J
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Feber, Andrew
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Fenton, Tim R.
98dfc021-d0ba-4562-81a6-2baea646dd0b
Chakravarthy, Ankur
736774ce-5094-45d8-a148-aaa35466297e
Furness, Andrew
0058746f-23f6-463d-94df-ccbb8d6513a2
Joshi, Kroopa
48c0bcbb-88f7-405d-b5f3-4126ab80b67a
Ghorani, Ehsan
4dfd1d77-5b23-477f-8d54-21ec52220f5e
Ford, Kirsty
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Ward, Matthew J.
9ba2223e-bb17-43a5-87b0-826a59e3a73a
King, Emma V.
d85e0e8f-7295-4912-9052-646a790d99db
Lechner, Matt
327faa2a-e083-46bb-8da6-337114f3a172
Marafioti, Teresa
2036b6e2-1157-4170-a533-a7c2307d619b
Quezada, Sergio A.
0f0f9dab-6569-472e-8bb3-39b63c989008
Thomas, Gareth J
2ff54aa9-a766-416b-91ee-cf1c5be74106
Feber, Andrew
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Fenton, Tim R.
98dfc021-d0ba-4562-81a6-2baea646dd0b

Chakravarthy, Ankur, Furness, Andrew, Joshi, Kroopa, Ghorani, Ehsan, Ford, Kirsty, Ward, Matthew J., King, Emma V., Lechner, Matt, Marafioti, Teresa, Quezada, Sergio A., Thomas, Gareth J, Feber, Andrew and Fenton, Tim R. (2018) Pan-cancer deconvolution of tumour composition using DNA methylation. Nature Communications, 9 (3220), 1-13. (doi:10.1038/s41467-018-05570-1).

Record type: Article

Abstract

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: ‘immune hot’ and ‘immune cold’, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.

Text
Chakravarthy et al., 2018 - Version of Record
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 10 July 2018
e-pub ahead of print date: 13 August 2018
Published date: 2018

Identifiers

Local EPrints ID: 423107
URI: https://eprints.soton.ac.uk/id/eprint/423107
PURE UUID: 3de6c609-2a20-4f5d-bae5-7b4c11e5d9ae

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Date deposited: 14 Aug 2018 16:30
Last modified: 13 Mar 2019 18:10

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