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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-11-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-021-00570-9 |
| _version_ | 1831677266454642688 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T04:39:36Z |
| format | Article |
| id | doaj.art-732acc4b856f474288360cfb1b5493f3 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-12-20T04:39:36Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-732acc4b856f474288360cfb1b5493f32022-12-21T19:53:10ZengNature Publishing GroupBlood Cancer Journal2044-53852021-11-01111111010.1038/s41408-021-00570-9Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypesJames B. Studd0Alex J. Cornish1Phuc H. Hoang2Philip Law3Ben Kinnersley4Richard Houlston5Division of Genetics and Epidemiology, The Institute of Cancer ResearchDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDivision of Genetics and Epidemiology, The Institute of Cancer ResearchAbstract 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.https://doi.org/10.1038/s41408-021-00570-9 |
| spellingShingle | 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 Blood Cancer Journal |
| title | 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_short | Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes |
| title_sort | cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes |
| url | https://doi.org/10.1038/s41408-021-00570-9 |
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