Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
Authors: 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, Ariana Huebner, Corentin Richard, Crispin T. Hiley, Emilia L. Lim, Francisco Gimeno-Valiente, Krupa Thakkar, Maise Al Bakir, Monica Sivakumar, Ieva Usaite, Sadegh Saghafinia, Sharon Vanloo, Sian Harries, Antonia Toncheva, Paulina Prymas, Bushra Mussa, Michalina Magala, Elizabeth Keene, Abigail Bunkum, Carlos Martínez-Ruiz, Clare Puttick, Despoina Karagianni, James R. M. Black, Kerstin Thol, Nicholas McGranahan, Olivia Lucas, Robert Bentham, Roberto Vendramin, Sergio A. Quezada, Simone Zaccaria, Sonya Hessey, Supreet Kaur Bola, Wing Kin Liu, Rija Zaidi, Lucrezia Patruno, Martin D. Forster, Siow Ming Lee, Gareth A. Wilson, Rachel Rosenthal, Andrew Rowan, Chris Bailey, Claudia Lee, Katey S. S. Enfield, Mihaela Angelova, Oriol Pich, Cian Murphy, Maria Zagorulya, Michelle M. Leung, Teresa Marafioti, Elaine Borg, Mary Falzon, Reena Khiroya, Thomas Patrick Jones, Sarah Benafif, Dionysis Papadatos-Pastos, James Wilson, Tanya Ahmad, Angela Dwornik, Angeliki Karamani, Benny Chain, David R. Pearce, Georgia Stavrou, Gerasimos-Theodoros Mastrokalos, Helen L. Lowe, James L. Reading, John A. Hartley, Kayalvizhi Selvaraju, Leah Ensell, Mansi Shah, Maria Litovchenko, Piotr Pawlik, Samuel Gamble, Seng Kuong Anakin Ung, Victoria Spanswick, Clare E. Weeden, Eva Grönroos, Jacki Goldman, Mickael Escudero, Philip Hobson, Stefan Boeing, Tamara Denner, Vittorio Barbè, William Hill, Yutaka Naito, Erik Sahai, Zoe Ramsden, George Kassiotis, Imran Noorani, Jason F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Mohamad Tufail, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Sean Dulloo, Dean A. Fennell, Claire Wilson, Gurdeep Matharu, Jacqui A. Shaw, Ekaterini Boleti, Heather Cheyne, Mohammed Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Jack French, Kayleigh Gilbert, Babu Naidu, Akshay J. Patel, Aya Osman, Mandeesh Sangha, Gerald Langman, Helen Shackleford, Madava Djearaman, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nicola Totton, Eustace Fontaine, Felice Granato, Juliette Novasio, Kendadai Rammohan, Leena Joseph, Paul Bishop, Vijay Joshi, Sara Waplington, Adam Atkin, Antonio Paiva-Correia, Philip Crosbie, Katherine D. Brown, Mathew Carter, Anshuman Chaturvedi, Pedro Oliveira, Colin R. Lindsay, Fiona H. Blackhall, Yvonne Summers, Matthew G. Krebs, Jonathan Tugwood, Caroline Dive, Hugo J. W. L. Aerts, Roland F. Schwarz, Tom L. Kaufmann, Peter Van Loo, Carla Castignani, Roberto Salgado, Miklos Diossy, Jonas Demeulemeester, Stephan Beck, Emma Nye, Richard Kevin Stone, Jayant K. Rane, Jeanette Kittel, Kerstin Haase, Kexin Koh, Rachel Scott, Karl S. Peggs, Emilie Martinoni Hoogenboom, Fleur Monk, James W. Holding, Junaid Choudhary, Kunal Bhakhri, Pat Gorman, Robert C. M. Stephens, Yien Ning Sophia Wong, Maria Chiara Pisciella, Steve Bandula, Thomas B. K. Watkins, Catarina Veiga, Gary Royle, Charles-Antoine Collins-Fekete, Francesco Fraioli, Paul Ashford, Alexander James Procter, Asia Ahmed, Magali N. Taylor, Arjun Nair, David Lawrence, Davide Patrini, Neal Navani, Ricky M. Thakrar, Sam M. Janes, Zoltan Kaplar, Allan Hackshaw, Camilla Pilotti, Rachel Leslie, Anne-Marie Hacker, Sean Smith, Aoife Walker, Anca Grapa, Hanyun Zhang, Khalid AbdulJabbar, Xiaoxi Pan, Yinyin Yuan, David Chuter, Mairead MacKenzie, Serena Chee, Patricia Georg, Aiman Alzetani, Judith Cave, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Lyn Ambrose, Anand Devaraj, Hemangi Chavan, Sofina Begum, Silviu I. Buderi, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G. Nicholson, Nadia Fernandes, Pratibha Shah, Chiara Proli, Madeleine Hewish, Sarah Danson, Michael J. Shackcloth, Lily Robinson, Peter Russell, Kevin G. Blyth, Andrew Kidd, Craig Dick, John Le Quesne, Alan Kirk, Mo Asif, Rocco Bilancia, Nikos Kostoulas, Jennifer Whiteley, Mathew Thomas, Allan Hackshaw, Mariam Jamal-Hanjani, Nnennaya Kanu, Nicolai J. Birkbak, Charles Swanton
Journal: Nature Cancer (2025)

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.