eprintid: 10203594 rev_number: 21 eprint_status: archive userid: 699 dir: disk0/10/20/35/94 datestamp: 2025-01-20 10:25:56 lastmod: 2025-06-16 09:58:45 status_changed: 2025-01-20 10:25:56 type: article metadata_visibility: show sword_depositor: 699 creators_name: Biswas, Dhruva creators_name: Liu, Yun-Hsin creators_name: Herrero, Javier creators_name: Wu, Yin creators_name: Moore, David A creators_name: Karasaki, Takahiro creators_name: Grigoriadis, Kristiana creators_name: Lu, Wei-Ting creators_name: Veeriah, Selvaraju creators_name: Naceur-Lombardelli, Cristina creators_name: Magno, Neil creators_name: Ward, Sophia creators_name: Frankell, Alexander M creators_name: Hill, Mark S creators_name: Colliver, Emma creators_name: De Carné Trécesson, Sophie creators_name: East, Philip creators_name: Malhi, Aman creators_name: Snell, Daniel M creators_name: O'Neill, Olga creators_name: Leonce, Daniel creators_name: Mattsson, Johanna creators_name: Lindberg, Amanda creators_name: Micke, Patrick creators_name: Moldvay, Judit creators_name: Megyesfalvi, Zsolt creators_name: Dome, Balasz creators_name: Fillinger, János creators_name: Nicod, Jerome creators_name: Downward, Julian creators_name: Szallasi, Zoltan creators_name: TRACERx Consortium, creators_name: Hackshaw, Allan creators_name: Jamal-Hanjani, Mariam creators_name: Kanu, Nnennaya creators_name: Birkbak, Nicolai J creators_name: Swanton, Charles title: Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma adenocarcinoma ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D19 divisions: H01 divisions: G99 keywords: Cancer, Cancer genomics, Non-small-cell lung cancer, Tumour biomarkers note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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. date: 2025-01 date_type: published publisher: Springer Science and Business Media LLC official_url: https://doi.org/10.1038/s43018-024-00883-1 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2342860 doi: 10.1038/s43018-024-00883-1 medium: Print-Electronic pii: 10.1038/s43018-024-00883-1 lyricists_name: Kanu, Nnennaya lyricists_name: Swanton, Robert lyricists_name: Ward, Sophia lyricists_name: Hackshaw, Allan lyricists_name: Jamal-Hanjani, Mariam lyricists_name: Veeriah, Selvaraju lyricists_name: Moore, David lyricists_name: Liu, Yun-Hsin lyricists_id: NKANU55 lyricists_id: CSWAN79 lyricists_id: SWARD17 lyricists_id: AHACK11 lyricists_id: MJAMA72 lyricists_id: RVEER62 lyricists_id: DMOOR09 lyricists_id: YLIUK15 actors_name: Hackshaw, Allan actors_id: AHACK11 actors_role: owner funding_acknowledgements: C11496/A17786, C416/A21999 [Cancer Research UK (CRUK)]; EDDCPJT\100008 [Cancer Research UK (CRUK)]; EDDCPJT\100008 [Cancer Research UK (CRUK)]; EDDCPJT\100008 [Cancer Research UK (CRUK)]; EDDCPJT\100008 [Cancer Research UK (CRUK)]; CC2041 [Wellcome Trust]; CC2041 [Wellcome Trust]; CC2041 [Wellcome Trust]; 220589/Z/20/Z [Wellcome Trust (Wellcome)]; ID16584 [Novo Nordisk Foundation Center for Basic Metabolic Research (NovoNordisk Foundation Center for Basic Metabolic Research)]; 202060447 [Japan Society for the Promotion of Science London (JSPS London)]; Bolyai Research Scholarship [Hungarian Academy of Sciences | Magyar Tudományos Akadémia Számítástechnikai és Automatizálási Kutatóintézet (Számítástechnikai és Automatizálási Kutatóintézet)]; Young Investigator Grant [International Association for the Study of Lung Cancer (IASLC)]; I4677 [Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)]; UCL/12/0279 [University College London (UCL)] full_text_status: public publication: Nature Cancer volume: 6 pagerange: 86-101 event_location: England issn: 2662-1347 citation: Biswas, Dhruva; Liu, Yun-Hsin; Herrero, Javier; Wu, Yin; Moore, David A; Karasaki, Takahiro; Grigoriadis, Kristiana; ... Swanton, Charles; + view all <#> Biswas, Dhruva; Liu, Yun-Hsin; Herrero, Javier; Wu, Yin; Moore, David A; Karasaki, Takahiro; Grigoriadis, Kristiana; Lu, Wei-Ting; Veeriah, Selvaraju; Naceur-Lombardelli, Cristina; Magno, Neil; Ward, Sophia; Frankell, Alexander M; Hill, Mark S; Colliver, Emma; De Carné Trécesson, Sophie; East, Philip; Malhi, Aman; Snell, Daniel M; O'Neill, Olga; Leonce, Daniel; Mattsson, Johanna; Lindberg, Amanda; Micke, Patrick; Moldvay, Judit; Megyesfalvi, Zsolt; Dome, Balasz; Fillinger, János; Nicod, Jerome; Downward, Julian; Szallasi, Zoltan; TRACERx Consortium; Hackshaw, Allan; Jamal-Hanjani, Mariam; Kanu, Nnennaya; Birkbak, Nicolai J; Swanton, Charles; - view fewer <#> (2025) Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma adenocarcinoma. Nature Cancer , 6 pp. 86-101. 10.1038/s43018-024-00883-1 <https://doi.org/10.1038/s43018-024-00883-1>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10203594/1/Hackshaw_s43018-024-00883-1.pdf