Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Abstract To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of bot...

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Autores principales:	James B. Studd, Alex J. Cornish, Phuc H. Hoang, Philip Law, Ben Kinnersley, Richard Houlston
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/732acc4b856f474288360cfb1b5493f3
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spelling	oai:doaj.org-article:732acc4b856f474288360cfb1b5493f32021-11-14T12:43:26ZCancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes10.1038/s41408-021-00570-92044-5385https://doaj.org/article/732acc4b856f474288360cfb1b5493f32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41408-021-00570-9https://doaj.org/toc/2044-5385Abstract To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a ‘hyperdiploid like’ subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.James B. StuddAlex J. CornishPhuc H. HoangPhilip LawBen KinnersleyRichard HoulstonNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBlood Cancer Journal, Vol 11, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 James B. Studd Alex J. Cornish Phuc H. Hoang Philip Law Ben Kinnersley Richard Houlston Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
description	Abstract To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a ‘hyperdiploid like’ subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.
format	article
author	James B. Studd Alex J. Cornish Phuc H. Hoang Philip Law Ben Kinnersley Richard Houlston
author_facet	James B. Studd Alex J. Cornish Phuc H. Hoang Philip Law Ben Kinnersley Richard Houlston
author_sort	James B. Studd
title	Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
title_short	Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
title_full	Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
title_fullStr	Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
title_full_unstemmed	Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
title_sort	cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/732acc4b856f474288360cfb1b5493f3
work_keys_str_mv	AT jamesbstudd cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes AT alexjcornish cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes AT phuchhoang cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes AT philiplaw cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes AT benkinnersley cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes AT richardhoulston cancerdriversandclonaldynamicsinacutelymphoblasticleukaemiasubtypes
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Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

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