Abstract
Original language | English |
---|---|
Pages (from-to) | 543-552 |
Number of pages | 10 |
Journal | Nature |
Volume | 616 |
Issue number | 7957 |
DOIs | |
Publication status | Published - 20 Apr 2023 |
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- 10.1038/s41586-023-05706-4Licence: CC BY
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In: Nature, Vol. 616, No. 7957, 20.04.2023, p. 543-552.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genomic–transcriptomic evolution in lung cancer and metastasis
AU - Martínez-Ruiz, Carlos
AU - Black, James R.M.
AU - Puttick, Clare
AU - Hill, Mark S.
AU - Demeulemeester, Jonas
AU - Larose Cadieux, Elizabeth
AU - Thol, Kerstin
AU - Jones, Thomas P.
AU - Veeriah, Selvaraju
AU - Naceur-Lombardelli, Cristina
AU - Toncheva, Antonia
AU - Prymas, Paulina
AU - Rowan, Andrew
AU - Ward, Sophia
AU - Cubitt, Laura
AU - Athanasopoulou, Foteini
AU - Pich, Oriol
AU - Karasaki, Takahiro
AU - Moore, David A.
AU - Salgado, Roberto
AU - Colliver, Emma
AU - Castignani, Carla
AU - Dietzen, Michelle
AU - Huebner, Ariana
AU - Al Bakir, Maise
AU - Tanic, Miljana
AU - Watkins, Thomas B.K.
AU - Lim, Emilia L.
AU - Al-Rashed, Ali M.
AU - Lang, Danny
AU - Clements, James
AU - Cook, Daniel E.
AU - Rosenthal, Rachel
AU - Wilson, Gareth A.
AU - Frankell, Alexander M.
AU - de Carné Trécesson, Sophie
AU - East, Philip
AU - Kanu, Nnennaya
AU - Litchfield, Kevin
AU - Birkbak, Nicolai J.
AU - Hackshaw, Allan
AU - Beck, Stephan
AU - Van Loo, Peter
AU - Jamal-Hanjani, Mariam
AU - McGranahan, Nicholas
AU - Swanton, Charles
AU - Aerts , Hugo J.W.L.
AU - TRACERx Consortium
N1 - Funding Information: The TRACERx study (Clinicaltrials.gov number NCT01888601 ) is sponsored by University College London (UCL/12/0279) and has been approved by an independent research ethics committee (13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK) (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study; all site personnel, investigators, funders and industry partners who supported the generation of the data within this study; and staff at the Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology departments at the Francis Crick Institute. This work was supported by the Cancer Research UK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233), as well as the UCL Experimental Cancer Medicine Centre. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). For the generation of the RRBS data, we acknowledge technical support from the CRUK–UCL Centre-funded Genomics and Genome Engineering Core Facility of the UCL Cancer Institute and grant support from the NIHR BRC (BRC275/CN/SB/101330) and the Wellcome Trust (218274/Z/19/Z). N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant number 211179/Z/18/Z) and receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). C.S. is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US); and The Mark Foundation for Cancer Research Aspire Award (Grant 21-029-ASP). This work was supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant number SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). C.M.-R. is supported by the Rosetrees (M630) and Wellcome trusts. J.R.M.B. is supported by Cancer Research UK. C.P. is supported by the Francis Crick Institute. M.S.H. is supported by Cancer Research UK (TRACERx (C11496/A17786)). M.J.-H. is a Cancer Research UK Career Establishment Awardee and has received funding from CRUK, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Centre. J.D. is a postdoctoral fellow of the European Union’s Horizon 2020 research programme (Marie Sklodowska-Curie Grant Agreement No. 703594-DECODE) and the Research Foundation–Flanders (FWO 12J6916N). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). T.K. is supported by a JSPS Overseas Research Fellowships Program (202060447). J.D., E.L.C., C.C. and P.V.L. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2008), the UK Medical Research Council (CC2008) and the Wellcome Trust (CC2008). T.B.K.W. is supported by the Francis Crick Institute, as well as the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), the Breast Cancer Research Foundation (BCRF), a Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. M.A.B. is supported by Cancer Research UK, the Rosetrees Trust and the Francis Crick Institute. M.D. is supported by Cancer Research UK and the Lung Cancer Centre of Excellence. A.?Huebner is supported by Cancer Research UK. E.L.L. receives funding from the NovoNordisk Foundation (ID 16584). N.J.B. is a fellow of the Lundbeck Foundation (R272-2017-4040) and acknowledges funding from Aarhus University Research Foundation (AUFF-E-2018-7-14) and the Novo Nordisk Foundation (NNF21OC0071483).R.R. is supported by a Royal Society Research Professorships Enhancement Award (RP/EA/180007). K.L. is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), Rosetrees Trust and Cotswold Trust (A2437) and Cancer Research UK (C69256/A30194). E.C. is funded by Cancer Research UK (TRACERx (C11496/A17786)) and the Francis Crick Institute. S.d.C.T. was funded in part by a Marie Sklodowska-Curie Individual Fellowship from the European Union (MSCA-IF-2015-EF-ST 703228-iGEMMdev). A.M.F. is supported by Stand Up To Cancer (SU2C-AACR-DT23-17). A.R. is supported by the Francis Crick Institute.D.A.M. is supported the cancer Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025). Funding Information: The TRACERx study (Clinicaltrials.gov number NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent research ethics committee (13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK) (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study; all site personnel, investigators, funders and industry partners who supported the generation of the data within this study; and staff at the Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology departments at the Francis Crick Institute. This work was supported by the Cancer Research UK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233), as well as the UCL Experimental Cancer Medicine Centre. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). For the generation of the RRBS data, we acknowledge technical support from the CRUK–UCL Centre-funded Genomics and Genome Engineering Core Facility of the UCL Cancer Institute and grant support from the NIHR BRC (BRC275/CN/SB/101330) and the Wellcome Trust (218274/Z/19/Z). N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant number 211179/Z/18/Z) and receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). C.S. is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US); and The Mark Foundation for Cancer Research Aspire Award (Grant 21-029-ASP). This work was supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant number SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). C.M.-R. is supported by the Rosetrees (M630) and Wellcome trusts. J.R.M.B. is supported by Cancer Research UK. C.P. is supported by the Francis Crick Institute. M.S.H. is supported by Cancer Research UK (TRACERx (C11496/A17786)). M.J.-H. is a Cancer Research UK Career Establishment Awardee and has received funding from CRUK, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Centre. J.D. is a postdoctoral fellow of the European Union’s Horizon 2020 research programme (Marie Sklodowska-Curie Grant Agreement No. 703594-DECODE) and the Research Foundation–Flanders (FWO 12J6916N). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). T.K. is supported by a JSPS Overseas Research Fellowships Program (202060447). J.D., E.L.C., C.C. and P.V.L. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2008), the UK Medical Research Council (CC2008) and the Wellcome Trust (CC2008). T.B.K.W. is supported by the Francis Crick Institute, as well as the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), the Breast Cancer Research Foundation (BCRF), a Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. M.A.B. is supported by Cancer Research UK, the Rosetrees Trust and the Francis Crick Institute. M.D. is supported by Cancer Research UK and the Lung Cancer Centre of Excellence. A.?Huebner is supported by Cancer Research UK. E.L.L. receives funding from the NovoNordisk Foundation (ID 16584). N.J.B. is a fellow of the Lundbeck Foundation (R272-2017-4040) and acknowledges funding from Aarhus University Research Foundation (AUFF-E-2018-7-14) and the Novo Nordisk Foundation (NNF21OC0071483).R.R. is supported by a Royal Society Research Professorships Enhancement Award (RP/EA/180007). K.L. is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), Rosetrees Trust and Cotswold Trust (A2437) and Cancer Research UK (C69256/A30194). E.C. is funded by Cancer Research UK (TRACERx (C11496/A17786)) and the Francis Crick Institute. S.d.C.T. was funded in part by a Marie Sklodowska-Curie Individual Fellowship from the European Union (MSCA-IF-2015-EF-ST 703228-iGEMMdev). A.M.F. is supported by Stand Up To Cancer (SU2C-AACR-DT23-17). A.R. is supported by the Francis Crick Institute.D.A.M. is supported the cancer Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025). Publisher Copyright: © 2023, The Author(s).
PY - 2023/4/20
Y1 - 2023/4/20
N2 - Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
AB - Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
U2 - 10.1038/s41586-023-05706-4
DO - 10.1038/s41586-023-05706-4
M3 - Article
C2 - 37046093
SN - 0028-0836
VL - 616
SP - 543
EP - 552
JO - Nature
JF - Nature
IS - 7957
ER -