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