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Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

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journal contribution
posted on 2025-01-30, 11:42 authored by 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, TRACERx Consortium, Allan Hackshaw, Mariam Jamal-Hanjani, Nnennaya Kanu, Nicolai J Birkbak, Charles Swanton
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.

Funding

Crick (Grant ID: CC2097, Grant title: Downward CC2097) Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC1064, Grant title: STP Genomics) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC2040, Grant title: Sahai CC2040) Crick (Grant ID: CC2088, Grant title: Kassiotis CC2088) Crick (Grant ID: CC2008, Grant title: Van Loo CC2008) Crick (Grant ID: CC1119, Grant title: STP Scientific Computing) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC1062, Grant title: STP Flow Cytometry) Medical Research Council (Grant ID: MC_PC_17179, Grant title: CiC 2017: Crick Idea to Innovation (i2i)) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584)

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