Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.
Creators: name: Biswas, Dhruva
name: Liu, Yun-Hsin
name: Herrero, Javier
name: Wu, Yin
name: Moore, David A
name: Karasaki, Takahiro
name: Grigoriadis, Kristiana
name: Lu, Wei-Ting
name: Veeriah, Selvaraju
name: Naceur-Lombardelli, Cristina
name: Magno, Neil
name: Ward, Sophia
name: Frankell, Alexander M
name: Hill, Mark S
name: Colliver, Emma
name: de Carné Trécesson, Sophie
name: East, Philip
name: Malhi, Aman
name: Snell, Daniel M
name: O'Neill, Olga
name: Leonce, Daniel
name: Mattsson, Johanna
name: Lindberg, Amanda
name: Micke, Patrick
name: Moldvay, Judit
name: Megyesfalvi, Zsolt
name: Dome, Balazs
name: Fillinger, János
name: Nicod, Jerome
name: Downward, Julian
name: Szallasi, Zoltan
name: Consortium, TRACERx
name: Hackshaw, Allan
name: Jamal-Hanjani, Mariam
name: Kanu, Nnennaya
name: Birkbak, Nicolai J
name: Swanton, Charles
Publisher: name: The Francis Crick Institute
Year: 2025
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Chemical Biology & High Throughput
subject: Chemical Biology &amp; High Throughput
classificationCode: Ecology,Evolution & Ethology
subject: Ecology,Evolution &amp; Ethology
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms
classificationCode: Cell Biology
subject: Cell Biology
classificationCode: Imaging
subject: Imaging
classificationCode: Cell Cycle & Chromosomes
subject: Cell Cycle &amp; Chromosomes

description: 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.