Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
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.
Authors
- Hugo J.W.L. Aerts (ORCID: https://orcid.org/0000-0002-2122-2003)
- Cristina Naceur‐Lombardelli (ORCID: https://orcid.org/0000-0002-7097-0307)
- Teresa Marafioti (ORCID: https://orcid.org/0000-0003-1223-6275)
- Clare E. Weeden (ORCID: https://orcid.org/0000-0002-1561-1416)
- Jack Davies Hodgkinson
- Paulo De Sousa (ORCID: https://orcid.org/0000-0003-3011-4116)
- Kate Brown (ORCID: https://orcid.org/0009-0007-5006-8379)
- Reena Khiroya
- Tamara Denner
- Claudia Lee (ORCID: https://orcid.org/0000-0003-1715-2265)
- Xiaoxi Pan (ORCID: https://orcid.org/0000-0002-6146-5771)
- Seng Kuong Anakin Ung (ORCID: https://orcid.org/0009-0007-7231-0461)
- Mickael Escudero (ORCID: https://orcid.org/0000-0002-1336-815X)
- Pratibha Shah
- Richard Stone (ORCID: https://orcid.org/0000-0001-8059-3800)
- Gary Royle (ORCID: https://orcid.org/0000-0002-8548-7684)
- Corentin Richard (ORCID: https://orcid.org/0000-0001-9732-0219)
- Robert Stephens (ORCID: https://orcid.org/0000-0002-7510-1143)
- Hemangi Chavan
- Yinyin Yuan (ORCID: https://orcid.org/0000-0002-8556-4707)
- Julian Downward (ORCID: https://orcid.org/0000-0002-2331-4729)
- Sergio A. Quezada (ORCID: https://orcid.org/0000-0002-9763-1700)
- Aiman Alzetani (ORCID: https://orcid.org/0000-0002-3373-6714)
- William Hill (ORCID: https://orcid.org/0000-0002-9591-1389)
- Babu Naidu
- Jayant K. Rane (ORCID: https://orcid.org/0000-0002-9594-3938)
- Simone Zaccaria (ORCID: https://orcid.org/0000-0002-5265-7392)
- Wei-Ting Lu (ORCID: https://orcid.org/0000-0002-1405-4806)
- Nikos Kostoulas
- Roberto Salgado (ORCID: https://orcid.org/0000-0002-1110-3801)
- Neal Navani (ORCID: https://orcid.org/0000-0002-6412-7516)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Hilgardt Raubenheimer
- Takahiro Karasaki (ORCID: https://orcid.org/0000-0001-6863-2360)
- Mark S. Hill (ORCID: https://orcid.org/0000-0003-0718-8934)
- Maria Litovchenko (ORCID: https://orcid.org/0000-0003-1868-4933)
- Ekaterini Boleti
- Andrew J. Atkin (ORCID: https://orcid.org/0000-0002-3819-3448)
- Yutaka Naito (ORCID: https://orcid.org/0000-0001-6827-601X)
- Camilla Pilotti
- Rachel Scott (ORCID: https://orcid.org/0000-0001-5847-3378)
- Sophia Ward (ORCID: https://orcid.org/0000-0002-6777-5279)
- Colin R. Lindsay (ORCID: https://orcid.org/0000-0001-8167-5461)
- Wing Kin Liu
- Allan Hackshaw (ORCID: https://orcid.org/0000-0002-5570-5070)
- Alexander James Procter
- Paulina Prymas
- Katey S.S. Enfield (ORCID: https://orcid.org/0000-0002-4551-6073)
- James R. Black (ORCID: https://orcid.org/0000-0001-5598-7752)
- Jonas Demeulemeester (ORCID: https://orcid.org/0000-0002-2660-2478)
- Rebecca Boyles (ORCID: https://orcid.org/0000-0003-0073-6854)
- Zoltán Szállási (ORCID: https://orcid.org/0000-0001-5395-7509)
- Nikki Totton (ORCID: https://orcid.org/0000-0002-1900-2773)
- Olivia Lucas (ORCID: https://orcid.org/0000-0001-8169-7767)
- Alexandra Rice (ORCID: https://orcid.org/0000-0002-0527-7960)
- Anshuman Chaturvedi (ORCID: https://orcid.org/0000-0003-1575-1176)
- Oriol Pich (ORCID: https://orcid.org/0000-0002-1956-1882)
- Jeanette Kittel (ORCID: https://orcid.org/0000-0002-8964-4640)
- Gareth A. Wilson (ORCID: https://orcid.org/0000-0002-5703-9710)
- Daniel M. Snell (ORCID: https://orcid.org/0000-0002-0105-8437)
- David Lawrence (ORCID: https://orcid.org/0000-0002-3664-8832)
- Vittorio Barbè
- Jacki Goldman (ORCID: https://orcid.org/0000-0002-2981-5022)
- Maise Al Bakir (ORCID: https://orcid.org/0000-0002-0846-8332)
- David R. Pearce (ORCID: https://orcid.org/0000-0001-8443-2924)
- Kwang Cheol Koh (ORCID: https://orcid.org/0000-0002-9146-450X)
- Elaine Borg (ORCID: https://orcid.org/0000-0001-5930-2239)
- Mairead MacKenzie
- Jérôme Nicod (ORCID: https://orcid.org/0000-0003-2459-3480)
- Andrew Kidd (ORCID: https://orcid.org/0000-0003-1691-4395)
- Lily Robinson
- Anand Devaraj
- Roberto Vendramin (ORCID: https://orcid.org/0000-0001-7191-4887)
- Hanyun Zhang (ORCID: https://orcid.org/0000-0002-4140-7881)
- Sarah Benafif (ORCID: https://orcid.org/0000-0003-1407-1697)
- Emma Nye (ORCID: https://orcid.org/0000-0001-9154-3526)
- Sonya Hessey (ORCID: https://orcid.org/0000-0001-9856-424X)
- Crispin T. Hiley (ORCID: https://orcid.org/0000-0002-5869-0775)
- Alexander M. Frankell (ORCID: https://orcid.org/0000-0002-0341-7878)
- Krupa Thakkar
- Abigail Bunkum (ORCID: https://orcid.org/0000-0002-7753-9421)
- Anca Grapa
- Apostolos Nakas (ORCID: https://orcid.org/0000-0001-6993-1514)
- Yien Ning Sophia Wong (ORCID: https://orcid.org/0000-0003-1903-6110)
- Francesco Fraioli (ORCID: https://orcid.org/0000-0003-0821-6327)
- Gary Middleton (ORCID: https://orcid.org/0000-0001-5695-3474)
- C. Donovan Bailey (ORCID: https://orcid.org/0000-0002-3123-4083)
- Benny Chain (ORCID: https://orcid.org/0000-0002-7417-3970)
- Heather Cheyne
- Mary Falzon (ORCID: https://orcid.org/0009-0006-6210-4376)
- Caroline Dive (ORCID: https://orcid.org/0000-0002-1726-8850)
- Felice Granato
- Victoria J. Spanswick
- Amrita Bajaj (ORCID: https://orcid.org/0000-0002-9251-2753)
- Michelle Leung (ORCID: https://orcid.org/0000-0001-9555-1080)
- Molly Scotland
- Miklós Dióssy (ORCID: https://orcid.org/0000-0003-0308-6615)
- Amanda Lindberg (ORCID: https://orcid.org/0000-0001-8206-5294)
- Maria Zagorulya (ORCID: https://orcid.org/0000-0002-4478-5378)
- Emma Colliver (ORCID: https://orcid.org/0000-0002-1497-0740)
- Khalid AbdulJabbar (ORCID: https://orcid.org/0000-0002-4411-4435)
- Philip Hobson (ORCID: https://orcid.org/0000-0001-5117-2994)
- Clare Puttick (ORCID: https://orcid.org/0009-0006-3022-8737)
- Supreet Kaur Bola (ORCID: https://orcid.org/0000-0001-8558-8197)
- Jonathan Tugwood
- Sridhar Rathinam (ORCID: https://orcid.org/0000-0002-1065-0045)
- Rachel Rosenthal (ORCID: https://orcid.org/0000-0002-0900-8709)
- Leah Ensell
- Tom L. Kaufmann (ORCID: https://orcid.org/0000-0003-4374-1338)
- Georgia Stavrou (ORCID: https://orcid.org/0000-0002-8427-5233)
- Thomas B.K. Watkins (ORCID: https://orcid.org/0000-0001-7414-737X)
- Zsolt Megyesfalvi (ORCID: https://orcid.org/0000-0001-8552-6500)
- Aman Malhi
- Yin Wu (ORCID: https://orcid.org/0000-0003-4080-3935)
- Javier Herrero (ORCID: https://orcid.org/0000-0001-7313-717X)
- Dhruva Biswas (ORCID: https://orcid.org/0000-0001-9141-5188)
- Mihaela Angelova (ORCID: https://orcid.org/0000-0002-0495-9695)
- Yvonne Summers
- Mariam Jamal‐Hanjani (ORCID: https://orcid.org/0000-0003-1212-1259)
- Alan Kirk (ORCID: https://orcid.org/0000-0001-7317-523X)
- Rija Zaidi (ORCID: https://orcid.org/0000-0002-2259-4319)
- Gerald Langman
- Eva Grönroos (ORCID: https://orcid.org/0000-0001-8303-5409)
- Dionysis Papadatos-Pastos
- Lucrezia Patruno (ORCID: https://orcid.org/0000-0002-3721-9984)
- James M. Wilson (ORCID: https://orcid.org/0000-0002-9630-3131)
- Patrick Micke (ORCID: https://orcid.org/0000-0003-1210-5961)
- Zoe Ramsden
- Ieva Usaite (ORCID: https://orcid.org/0000-0001-6154-0447)
- Sara Waplington
- Angeliki Karamani
- Kerstin Thol (ORCID: https://orcid.org/0000-0002-4624-118X)
- Johanna Sofia Margareta Mattsson (ORCID: https://orcid.org/0000-0002-5294-7808)
- John A. Hartley (ORCID: https://orcid.org/0000-0003-3737-9897)
- Selvaraju Veeriah (ORCID: https://orcid.org/0000-0002-1217-0387)
- Andrew Rowan (ORCID: https://orcid.org/0000-0003-1926-9707)
- Nicholas McGranahan (ORCID: https://orcid.org/0000-0001-9537-4045)
- Balázs Döme (ORCID: https://orcid.org/0000-0001-8799-8624)
- Mpho Malima
- John Le Quesne (ORCID: https://orcid.org/0000-0003-3552-7446)
- George Kassiotis (ORCID: https://orcid.org/0000-0002-8457-2633)
- Michael Shackcloth (ORCID: https://orcid.org/0000-0002-6494-9907)
- Ricky M. Thakrar (ORCID: https://orcid.org/0000-0001-9793-2223)
- Kristiana Grigoriadis (ORCID: https://orcid.org/0000-0002-8435-0176)
- Philip East (ORCID: https://orcid.org/0000-0001-5801-5713)
- Neil Magno
- Aya Osman (ORCID: https://orcid.org/0000-0002-2048-5039)
- Angela Leek
- Despoina Karagianni (ORCID: https://orcid.org/0000-0002-8605-5808)
- Dean A. Fennell
- Sean Dulloo
- Fleur Monk
- Mathew Thomas (ORCID: https://orcid.org/0000-0002-2374-0146)
- Nnennaya Kanu (ORCID: https://orcid.org/0000-0001-7232-1952)
- Daniel Leonce
- Antonia Toncheva
- Davide Patrini (ORCID: https://orcid.org/0000-0002-2492-799X)
- Madava Djearaman
- Sophie de Carné Trécesson (ORCID: https://orcid.org/0000-0002-9341-2586)
- Samuel Gamble
- Sadegh Saghafinia (ORCID: https://orcid.org/0000-0001-5695-9825)
- Carlos Martínez‐Ruiz (ORCID: https://orcid.org/0000-0002-4817-0565)
- Juliette Novasio
- Maria Chiara Pisciella
- Elizabeth Keene
- Serena Chee (ORCID: https://orcid.org/0000-0001-7244-9876)
- Sam M. Janes (ORCID: https://orcid.org/0000-0002-6634-5939)
- Gurdeep Matharu
- Nadia J. Fernandes (ORCID: https://orcid.org/0000-0003-4595-9939)
- János Fillinger (ORCID: https://orcid.org/0000-0003-1877-8702)
- Francisco Gimeno-Valiente (ORCID: https://orcid.org/0000-0003-0544-9459)
- Sean Smith (ORCID: https://orcid.org/0000-0001-6758-4037)
- Jacqui Shaw (ORCID: https://orcid.org/0000-0003-4227-503X)
- Emilie Martinoni Hoogenboom
- António Paiva‐Correia (ORCID: https://orcid.org/0000-0001-8725-0202)
- Helen L. Lowe (ORCID: https://orcid.org/0000-0001-8630-378X)
- David Allan Moore (ORCID: https://orcid.org/0000-0002-6296-1312)
- Angela Dwornik
- Junaid Choudhary
- Mathew Carter
- Roland F. Schwarz (ORCID: https://orcid.org/0000-0001-9155-4268)
- Akshay Jatin Patel (ORCID: https://orcid.org/0000-0001-9170-8618)
- Sarah Danson (ORCID: https://orcid.org/0000-0002-3593-2890)
- Sofina Begum (ORCID: https://orcid.org/0000-0001-7689-0087)
- Pat Gorman
- Philip Crosbie
- Stephan Beck
- Mohamad Tufail
- Gillian Price
- J.F. Lester (ORCID: https://orcid.org/0000-0002-2311-070X)
- Harshil Bhayani
- Carla Castignani (ORCID: https://orcid.org/0000-0001-8689-9659)
- Silviu Buderi
- James W. Holding
- Ariana Huebner
- Kayalvizhi Selvaraju
- Rachel Leslie
- Stefan Boeing (ORCID: https://orcid.org/0000-0003-0495-5659)
- Rocco Bilancia
- Arjun Nair (ORCID: https://orcid.org/0000-0001-9270-3771)
- Erik Sahai (ORCID: https://orcid.org/0000-0002-3932-5086)
- Kendadai Rammohan
- Zoltán Káplár
- Catarina Veiga (ORCID: https://orcid.org/0000-0002-0911-152X)
- Azmina Sodha-Ramdeen
- Martin Förster (ORCID: https://orcid.org/0000-0003-3876-7269)
- Imran Noorani (ORCID: https://orcid.org/0000-0003-4289-2345)
- Vijay Joshi (ORCID: https://orcid.org/0000-0001-6803-4379)
- Nicolai J. Birkbak (ORCID: https://orcid.org/0000-0003-1613-9587)
- Matthew Krebs (ORCID: https://orcid.org/0000-0001-7540-3064)
- Kerstin Haase (ORCID: https://orcid.org/0000-0002-0944-5618)
- Judit Moldvay (ORCID: https://orcid.org/0000-0001-9425-1748)
- Eric Lim (ORCID: https://orcid.org/0000-0002-9078-3226)
- Tracey Cruickshank
- Sharon Vanloo
- Cian Murphy
- Bashair M. Mussa (ORCID: https://orcid.org/0000-0002-1554-6319)
- Shirley Richardson
- Chiara Proli
- Kunal Bhakhri
- Amy S. Walker (ORCID: https://orcid.org/0000-0003-0140-0586)
- Madeleine Hewish
- Paul Ashford (ORCID: https://orcid.org/0000-0003-4079-0257)
- Daniel Kaniu
- Charles‐Antoine Collins‐Fekete (ORCID: https://orcid.org/0000-0003-2464-8795)
- Fiona Helen Blackhall (ORCID: https://orcid.org/0000-0001-8716-3395)
- James L. Reading (ORCID: https://orcid.org/0000-0001-5381-978X)
- Jennifer Whiteley
- Helen Shackleford
- Gerasimos-Theodoros Mastrokalos
- Yun-Hsin Liu (ORCID: https://orcid.org/0009-0001-1508-5276)
- Pedro Oliveira (ORCID: https://orcid.org/0000-0001-8912-2490)
- Mohammed S. Khalil (ORCID: https://orcid.org/0000-0002-1539-5629)
- Judith Cave (ORCID: https://orcid.org/0000-0002-1497-0310)
- Claire Wilson (ORCID: https://orcid.org/0000-0002-6401-2014)
- Piotr Pawlik (ORCID: https://orcid.org/0009-0008-7075-615X)
- Andrew G. Nicholson
- Mo Asif
- Asia Ahmed
- Jack French
- Siow Ming Lee
- Thomas Patrick Jones
- Anne-Marie Hacker
- Eustace Fontaine
- Kevin G. Blyth
- Robert Bentham
- Peter Van Loo
- Simon Jordan
- Tanya Ahmad
- Monica Sivakumar
- Olga O’Neill
- Mandeesh Sangha
- Magali N. Taylor
- S. Harries
- Kayleigh Gilbert
- Craig Dick
- Steve Bandula
- Mansi Shah
- Petra Georg
- Karl S. Peggs
- Lyn Ambrose
- Peter Russell
- Emilia L. Lim (ORCID: https://orcid.org/0009-0009-2954-1795)
- Keith M. Kerr
- Sarah Booth
- Leena Dennis Joseph (ORCID: https://orcid.org/0000-0002-9395-2961)
- David Chuter
- Michalina Magala
Institutions
- Semmelweis University (HU)
- Eötvös Loránd University (HU)
- Uppsala University (SE)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- University College Hospital (GB)
- Swansea Bay University Health Board (GB)
- Guy's Hospital (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Garvan Institute of Medical Research (AU)
- Institute of Cancer Research (GB)
- University of Liverpool (GB)
- University of Leicester (GB)
- Royal Free London NHS Foundation Trust (GB)
- University of Cologne (DE)
- King's College London (GB)
- Lund University (SE)
- University of Aberdeen (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Aarhus University (DK)
- Max Delbrück Center (DE)
- University of Szeged (HU)
- Royal Brompton & Harefield NHS Foundation Trust (GB)
- NHS Greater Glasgow and Clyde (GB)
- Singleton Hospital (GB)
- Peter MacCallum Cancer Centre (AU)
- Aberdeen Royal Infirmary (GB)
- Princess Alexandra Hospital NHS Trust (GB)
- The Francis Crick Institute (GB)
- Royal London Hospital (GB)
- Cancer Research UK (GB)
- Buda Health Center (HU)
- Golden Jubilee National Hospital (GB)
- Aarhus University Hospital (DK)
- University Hospitals of Leicester NHS Trust (GB)
- Whittington Hospital (GB)
- Harefield Hospital (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Surrey (GB)
- University of Manchester (GB)
- Maastricht University (NL)
- Liverpool Heart and Chest Hospital (GB)
- London Cancer (GB)
- Comprehensive Cancer Center Vienna (AT)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Manchester University NHS Foundation Trust (GB)
- NHS Grampian (GB)
- St Charles Hospital (GB)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- VIB-KU Leuven Center for Microbiology (BE)
- Dana-Farber Cancer Institute (US)
- NIHR Southampton Biomedical Research Centre (GB)
- National Institute of Oncology (HU)
- Cancer Research UK Manchester Institute (GB)
- The Christie NHS Foundation Trust (GB)
- National Cancer Centre Singapore (SG)
- Cancer Research UK Scotland Institute (GB)
- Immune Regulation (United Kingdom) (GB)
- Royal Surrey NHS Foundation Trust (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- Danish Cancer Society (DK)
- Wythenshawe Hospital (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Genomics (United Kingdom) (GB)
- Independent Age (GB)
- University Hospital Cologne (DE)
- Institute of Structural and Molecular Biology (GB)
- Queen Elizabeth University Hospital (GB)
- Dana-Farber Brigham Cancer Center (US)
- Országos Korányi Tbc és Pulmonológiai Intézet (HU)
- The Patients Association (GB)
- Toranomon Hospital (JP)
- Cancer Research UK Manchester Centre
- University College London (GB)
- Imperial College London (GB)
- Mass General Brigham (US)
- Medical University of Vienna (AT)
- University of Glasgow (GB)
- University of Birmingham (GB)
- University of Sheffield (GB)
- Stanford University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1038/s43018-024-00883-1
- Citations
- 9
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 13.67
Funders
- Breast Cancer Research Foundation
- International Association for the Study of Lung Cancer
- Wellcome Trust
- Francis Crick Institute
- Mark Foundation For Cancer Research
- Cancer Research UK
- National Institute for Health and Care Research
- University College London
- Rosetrees Trust
- Austrian Science Fund
- Magyar Tudományos Akadémia
- Innovációs és Technológiai Minisztérium
- CRUK Lung Cancer Centre of Excellence
- National Institutes of Health
- Medical Research Council
- Japan Society for the Promotion of Science
- National Research, Development and Innovation Office
- National Cancer Institute