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 Sofia Margareta Mattsson, Amanda Lindberg, Patrick Micke, Judit Moldvay, Zsolt Megyesfalvi, Balázs Döme, János Fillinger, Jérôme Nicod, Julian Downward, Zoltán Szállási, 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, S. Harries, Antonia Toncheva, Paulina Prymas, Bushra Mussa, Michalina Magala, Elizabeth Keene, Abigail Bunkum, Carlos Martínez‐Ruiz, Clare Puttick, Despoina Karagianni, James R. 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 Förster, Siow Ming Lee, Gareth A. Wilson, Rachel Rosenthal, Andrew Rowan, C. Donovan Bailey, Claudia Lee, Katey S.S. Enfield, Mihaela Angelova, Oriol Pich, Cian Murphy, Maria Zagorulya, Michelle Leung, Teresa Marafioti, Elaine Borg, Mary Falzon, Reena Khiroya, Thomas Patrick Jones, Sarah Benafif, Dionysis Papadatos-Pastos, James M. 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
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.