%V 6
%N 1
%O Online ahead of print. 
Published online: 09 January 2025
%J NATURE CANCER
%I szte
%A  Biswas Dhruva
%A  Liu Yun-Hsin
%A  Herrero Javier
%A  Snell Daniel M.
%A  O’Neill Olga
%A  Leonce Daniel
%A  Mattsson Johanna
%A  Lindberg Amanda
%A  Micke Patrick
%A  Moldvay Judit
%A  Megyesfalvi Zsolt
%A  DĂśme Balazs
%A  Fillinger JĂĄnos
%A  Nicod Jerome
%A  Downward Julian
%A  KollaborĂĄiĂłs szervezet: TRACERx Consortium
%A  et al.
%T Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
%R MTMT:35681466 10.1038/s43018-024-00883-1
%P 86-101
%L publicatio35541
%D 2025
%X 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.