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

Biswas, D; Liu, YH; Herrero, J; Wu, Y; Moore, DA; Karasaki, T; Grigoriadis, K; Lu, WT; Veeriah, S; Naceur-Lombardelli, C; Magno, N; Ward, S; Frankell, AM; Hill, MS; Colliver, E; de Carne Trecesson, S; East, P; Malhi, A; Snell, DM; O’Neill, O; Leonce, D; Mattsson, J; Lindberg, A; Micke, P; Moldvay, J; Megyesfalvi, Z; Dome, B; Fillinger, J; Nicod, J; Downward, J; Szallasi, Z; TRACERx Consortium; Hackshaw, A; Jamal-Hanjani, M; Kanu, N; Birkbak, NJ; Swanton, C

Author(s): Biswas, D; Liu, YH; Herrero, J; Wu, Y; Moore, DA; Karasaki, T; Grigoriadis, K; Lu, WT; Veeriah, S; Naceur-Lombardelli, C; Magno, N; Ward, S; Frankell, AM; Hill, MS; Colliver, E; de Carne Trecesson, S; East, P; Malhi, A; Snell, DM; O’Neill, O; Leonce, D; Mattsson, J; Lindberg, A; Micke, P; Moldvay, J; Megyesfalvi, Z; Dome, B; Fillinger, J; Nicod, J; Downward, J; Szallasi, Z; TRACERx Consortium; Hackshaw, A; Jamal-Hanjani, M; Kanu, N; Birkbak, NJ; Swanton, C;
Details: Publication Year 2025-01,Volume 6,Issue #1,Page 86-101
Journal Title: Nature Cancer
Publication Type: Research article
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.
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s43018-024-00883-1
Open Access at Publisher's Site: https://doi.org/10.1038/s43018-024-00883-1
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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