Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma

Dhruva Biswas; Yun Hsin Liu; Javier Herrero; Yin Wu; David A. Moore; Takahiro Karasaki; Kristiana Grigoriadis; Wei Ting Lu; Selvaraju Veeriah; Cristina Naceur-Lombardelli; Neil Magno; Sophia Ward; Alexander M. Frankell; Mark S. Hill; Emma Colliver; Sophie de Carné Trécesson; Philip East; Aman Malhi; Daniel M. Snell; Olga O’Neill; Daniel Leonce; Johanna Mattsson; Amanda Lindberg; Patrick Micke; Judit Moldvay; Zsolt Megyesfalvi; Balazs Dome; János Fillinger; Jerome Nicod; Julian Downward; Zoltan Szallasi; Mathew Thomas; Jennifer Whiteley; Nikos Kostoulas; Rocco Bilancia; Mo Asif; Alan Kirk; John Le Quesne; Craig Dick; Andrew Kidd; Kevin G. Blyth; Peter Russell; Lily Robinson; Michael J. Shackcloth; Sarah Danson; Madeleine Hewish; Chiara Proli; Pratibha Shah; Nadia Fernandes; Andrew G. Nicholson; TRACERx Consortium; Nicolai Birkbak; Charles Swanton; Hugo J.W.L. Aerts

doi:10.1038/s43018-024-00883-1

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma

Dhruva Biswas^*, Yun Hsin Liu, Javier Herrero, Yin Wu, David A. Moore, Takahiro Karasaki, Kristiana Grigoriadis, Wei Ting Lu, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Neil Magno, Sophia Ward, Alexander M. Frankell, Mark S. Hill, Emma Colliver, Sophie de Carné Trécesson, Philip East, Aman Malhi, Daniel M. Snell, Olga O’NeillDaniel Leonce, Johanna Mattsson, Amanda Lindberg, Patrick Micke, Judit Moldvay, Zsolt Megyesfalvi, Balazs Dome, János Fillinger, Jerome Nicod, Julian Downward, Zoltan Szallasi, Mathew Thomas, Jennifer Whiteley, Nikos Kostoulas, Rocco Bilancia, Mo Asif, Alan Kirk, John Le Quesne, Craig Dick, Andrew Kidd, Kevin G. Blyth, Peter Russell, Lily Robinson, Michael J. Shackcloth, Sarah Danson, Madeleine Hewish, Chiara Proli, Pratibha Shah, Nadia Fernandes, Andrew G. Nicholson, TRACERx Consortium, Nicolai Birkbak^*, Charles Swanton^*, Hugo J.W.L. Aerts

^*Corresponding author for this work

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

Abstract

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.

Original language	English
Article number	10110
Pages (from-to)	86-101
Journal	Nature Cancer
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s43018-024-00883-1
Publication status	Published - 1 Jan 2025

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Biswas, D., Liu, Y. H., Herrero, J., Wu, Y., Moore, D. A., Karasaki, T., Grigoriadis, K., Lu, W. T., Veeriah, S., Naceur-Lombardelli, C., Magno, N., Ward, S., Frankell, A. M., Hill, M. S., Colliver, E., de Carné Trécesson, S., East, P., Malhi, A., Snell, D. M., ... Aerts, H. J. W. L. (2025). Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma. Nature Cancer, 6(1), 86-101. Article 10110. https://doi.org/10.1038/s43018-024-00883-1

@article{59275e2658254678bd3c50636ee3a64a,

title = "Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma",

abstract = "Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.",

author = "Dhruva Biswas and Liu, {Yun Hsin} and Javier Herrero and Yin Wu and Moore, {David A.} and Takahiro Karasaki and Kristiana Grigoriadis and Lu, {Wei Ting} and Selvaraju Veeriah and Cristina Naceur-Lombardelli and Neil Magno and Sophia Ward and Frankell, {Alexander M.} and Hill, {Mark S.} and Emma Colliver and {de Carn{\'e} Tr{\'e}cesson}, Sophie and Philip East and Aman Malhi and Snell, {Daniel M.} and Olga O{\textquoteright}Neill and Daniel Leonce and Johanna Mattsson and Amanda Lindberg and Patrick Micke and Judit Moldvay and Zsolt Megyesfalvi and Balazs Dome and J{\'a}nos Fillinger and Jerome Nicod and Julian Downward and Zoltan Szallasi and Mathew Thomas and Jennifer Whiteley and Nikos Kostoulas and Rocco Bilancia and Mo Asif and Alan Kirk and {Le Quesne}, John and Craig Dick and Andrew Kidd and Blyth, {Kevin G.} and Peter Russell and Lily Robinson and Shackcloth, {Michael J.} and Sarah Danson and Madeleine Hewish and Chiara Proli and Pratibha Shah and Nadia Fernandes and Nicholson, {Andrew G.} and {TRACERx Consortium} and Nicolai Birkbak and Charles Swanton and Aerts, {Hugo J.W.L.}",

note = "Funding Information: The TRACERx study (ClinicalTrials.gov identifier 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 CRUK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We 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 the support of Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology Science Technology Platforms at the Francis Crick Institute. This work is also supported by the CRUK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as the UCL Experimental Cancer Medicine Centre. D.B. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008), the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre and the Breast Cancer Research Foundation (BCRF). Fig. 1a is created in BioRender.com (Biswas, D. (2024) BioRender.com/t56b560). Y.-H.L. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008). Y.W. is supported by funding from the Wellcome Trust (220589/Z/20/Z). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). J.M. is supported by the Hungarian National Research, Development and Innovation Office (K129065). B.D. is supported by the Austrian Science Fund (FWF I3522, FWF I3977, and I4677) and the \u2018BIOSMALL\u2019 EU HORIZON-MSCA-2022-SE-01 project. Z.M. is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP\u201020\u20103, UNKP\u201021\u20103 and UNKP-23-5), and by the Bolyai Research Scholarship of the Hungarian Academy of Sciences. Z.M. is also the recipient of an International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022). B.D. and Z.M. are supported by funding from the Hungarian National Research, Development, and Innovation Office (2020\u20101.1.6\u2010J\u00D6V\u0150, TKP2021\u2010EGA\u201033, FK\u2010143751 and FK-147045). M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). C.S. is supported by the Francis Crick Institute, which receives its core funding from CRUK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786)), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the NovoNordisk Foundation (ID16584), a Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, the CRUK\u2013University College London Centre, the Experimental Cancer Medicine Centre, the Breast Cancer Research Foundation (US) and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). Funding Information: The TRACERx study (ClinicalTrials.gov identifier 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 CRUK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We 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 the support of Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology Science Technology Platforms at the Francis Crick Institute. This work is also supported by the CRUK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as the UCL Experimental Cancer Medicine Centre. D.B. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008), the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre and the Breast Cancer Research Foundation (BCRF). Fig. is created in BioRender.com (Biswas, D. (2024) BioRender.com/t56b560). Y.-H.L. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008). Y.W. is supported by funding from the Wellcome Trust (220589/Z/20/Z). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). J.M. is supported by the Hungarian National Research, Development and Innovation Office (K129065). B.D. is supported by the Austrian Science Fund (FWF I3522, FWF I3977, and I4677) and the \u2018BIOSMALL\u2019 EU HORIZON-MSCA-2022-SE-01 project. Z.M. is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP\u201020\u20103, UNKP\u201021\u20103 and UNKP-23-5), and by the Bolyai Research Scholarship of the Hungarian Academy of Sciences. Z.M. is also the recipient of an International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022). B.D. and Z.M. are supported by funding from the Hungarian National Research, Development, and Innovation Office (2020\u20101.1.6\u2010J\u00D6V\u0150, TKP2021\u2010EGA\u201033, FK\u2010143751 and FK-147045). M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). C.S. is supported by the Francis Crick Institute, which receives its core funding from CRUK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786)), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the NovoNordisk Foundation (ID16584), a Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, the CRUK\u2013University College London Centre, the Experimental Cancer Medicine Centre, the Breast Cancer Research Foundation (US) and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jan,

day = "1",

doi = "10.1038/s43018-024-00883-1",

language = "English",

volume = "6",

pages = "86--101",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Publishing Group",

number = "1",

}

Biswas, D, Liu, YH, Herrero, J, Wu, Y, Moore, DA, Karasaki, T, Grigoriadis, K, Lu, WT, Veeriah, S, Naceur-Lombardelli, C, Magno, N, Ward, S, Frankell, AM, Hill, MS, Colliver, E, de Carné Trécesson, S, East, P, Malhi, A, Snell, DM, O’Neill, O, Leonce, D, Mattsson, J, Lindberg, A, Micke, P, Moldvay, J, Megyesfalvi, Z, Dome, B, Fillinger, J, Nicod, J, Downward, J, Szallasi, Z, Thomas, M, Whiteley, J, Kostoulas, N, Bilancia, R, Asif, M, Kirk, A, Le Quesne, J, Dick, C, Kidd, A, Blyth, KG, Russell, P, Robinson, L, Shackcloth, MJ, Danson, S, Hewish, M, Proli, C, Shah, P, Fernandes, N, Nicholson, AG, TRACERx Consortium, Birkbak, N, Swanton, C & Aerts, HJWL 2025, 'Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma', Nature Cancer, vol. 6, no. 1, 10110, pp. 86-101. https://doi.org/10.1038/s43018-024-00883-1

TY - JOUR

T1 - Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma

AU - Biswas, Dhruva

AU - Liu, Yun Hsin

AU - Herrero, Javier

AU - Wu, Yin

AU - Moore, David A.

AU - Karasaki, Takahiro

AU - Grigoriadis, Kristiana

AU - Lu, Wei Ting

AU - Veeriah, Selvaraju

AU - Naceur-Lombardelli, Cristina

AU - Magno, Neil

AU - Ward, Sophia

AU - Frankell, Alexander M.

AU - Hill, Mark S.

AU - Colliver, Emma

AU - de Carné Trécesson, Sophie

AU - East, Philip

AU - Malhi, Aman

AU - Snell, Daniel M.

AU - O’Neill, Olga

AU - Leonce, Daniel

AU - Mattsson, Johanna

AU - Lindberg, Amanda

AU - Micke, Patrick

AU - Moldvay, Judit

AU - Megyesfalvi, Zsolt

AU - Dome, Balazs

AU - Fillinger, János

AU - Nicod, Jerome

AU - Downward, Julian

AU - Szallasi, Zoltan

AU - Thomas, Mathew

AU - Whiteley, Jennifer

AU - Kostoulas, Nikos

AU - Bilancia, Rocco

AU - Asif, Mo

AU - Kirk, Alan

AU - Le Quesne, John

AU - Dick, Craig

AU - Kidd, Andrew

AU - Blyth, Kevin G.

AU - Russell, Peter

AU - Robinson, Lily

AU - Shackcloth, Michael J.

AU - Danson, Sarah

AU - Hewish, Madeleine

AU - Proli, Chiara

AU - Shah, Pratibha

AU - Fernandes, Nadia

AU - Nicholson, Andrew G.

AU - TRACERx Consortium

AU - Birkbak, Nicolai

AU - Swanton, Charles

AU - Aerts, Hugo J.W.L.

N1 - Funding Information: The TRACERx study (ClinicalTrials.gov identifier 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 CRUK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We 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 the support of Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology Science Technology Platforms at the Francis Crick Institute. This work is also supported by the CRUK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as the UCL Experimental Cancer Medicine Centre. D.B. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008), the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre and the Breast Cancer Research Foundation (BCRF). Fig. 1a is created in BioRender.com (Biswas, D. (2024) BioRender.com/t56b560). Y.-H.L. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008). Y.W. is supported by funding from the Wellcome Trust (220589/Z/20/Z). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). J.M. is supported by the Hungarian National Research, Development and Innovation Office (K129065). B.D. is supported by the Austrian Science Fund (FWF I3522, FWF I3977, and I4677) and the \u2018BIOSMALL\u2019 EU HORIZON-MSCA-2022-SE-01 project. Z.M. is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP\u201020\u20103, UNKP\u201021\u20103 and UNKP-23-5), and by the Bolyai Research Scholarship of the Hungarian Academy of Sciences. Z.M. is also the recipient of an International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022). B.D. and Z.M. are supported by funding from the Hungarian National Research, Development, and Innovation Office (2020\u20101.1.6\u2010J\u00D6V\u0150, TKP2021\u2010EGA\u201033, FK\u2010143751 and FK-147045). M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). C.S. is supported by the Francis Crick Institute, which receives its core funding from CRUK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786)), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the NovoNordisk Foundation (ID16584), a Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, the CRUK\u2013University College London Centre, the Experimental Cancer Medicine Centre, the Breast Cancer Research Foundation (US) and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). Funding Information: The TRACERx study (ClinicalTrials.gov identifier 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 CRUK and UCL Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We 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 the support of Scientific Computing, the Advanced Sequencing Facility and Experimental Histopathology Science Technology Platforms at the Francis Crick Institute. This work is also supported by the CRUK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as the UCL Experimental Cancer Medicine Centre. D.B. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008), the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre and the Breast Cancer Research Foundation (BCRF). Fig. is created in BioRender.com (Biswas, D. (2024) BioRender.com/t56b560). Y.-H.L. is supported by funding from a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award (EDDCPJT\\100008). Y.W. is supported by funding from the Wellcome Trust (220589/Z/20/Z). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). J.M. is supported by the Hungarian National Research, Development and Innovation Office (K129065). B.D. is supported by the Austrian Science Fund (FWF I3522, FWF I3977, and I4677) and the \u2018BIOSMALL\u2019 EU HORIZON-MSCA-2022-SE-01 project. Z.M. is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP\u201020\u20103, UNKP\u201021\u20103 and UNKP-23-5), and by the Bolyai Research Scholarship of the Hungarian Academy of Sciences. Z.M. is also the recipient of an International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022). B.D. and Z.M. are supported by funding from the Hungarian National Research, Development, and Innovation Office (2020\u20101.1.6\u2010J\u00D6V\u0150, TKP2021\u2010EGA\u201033, FK\u2010143751 and FK-147045). M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). C.S. is supported by the Francis Crick Institute, which receives its core funding from CRUK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786)), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the NovoNordisk Foundation (ID16584), a Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, the CRUK\u2013University College London Centre, the Experimental Cancer Medicine Centre, the Breast Cancer Research Foundation (US) and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). Publisher Copyright: © The Author(s) 2025.

PY - 2025/1/1

Y1 - 2025/1/1

N2 - Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.

AB - Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.

U2 - 10.1038/s43018-024-00883-1

DO - 10.1038/s43018-024-00883-1

M3 - Article

SN - 2662-1347

VL - 6

SP - 86

EP - 101

JO - Nature Cancer

JF - Nature Cancer

IS - 1

M1 - 10110

ER -

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma

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