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TRACERx 100: whole exome data of the first 100 TRACERx tumours

BACKGROUNDTRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC). METHODSMultiregion high-depth whole-exome sequencing (M-seq) was performed on 100 early stage NSCLC tumors resected prior to systemic therapy. A total of 327 tumor regions were sequenced and analyzed to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between ITH and recurrence-free survival (RFS). RESULTSWidespread ITH was observed for both somatic copy number alterations (median 48% [0.03-88%]) and mutations (median 30% [0.5-93%]). Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal. However, heterogeneous driver alterations occurring later in evolution were found in over 75% of tumors and were common in PIK3CA, NF1 and genes involved in chromatin modification and DNA response and repair. Genome doubling and ongoing dynamic chromosomal instability (CIN), illustrated by mirrored subclonal allelic imbalance, were identified as causes of ITH resulting in parallel evolution of driver copy number events, including amplifications of CDK4, FOXA1, and BCL11A. Elevated copy number heterogeneity was associated with shorter RFS (HR=4.9, P=0.00044), which remained significant in a multivariate analysis.CONCLUSIONSITH mediated through CIN, rather than point mutational heterogeneity, was associated with increased risk of relapse, supporting its value as a prognostic predictor, and the need to target this high-risk phenotype.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001003206 427
Publications Citations
Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.
Nature 545: 2017 446-451
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
Cell 171: 2017 1259-1271.e11
Genomic instability in mutant p53 cancer cells upon entotic engulfment.
Nat Commun 9: 2018 3070
A functional genetic screen defines the AKT-induced senescence signaling network.
Cell Death Differ 27: 2020 725-741
Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.
Nat Med 25: 2019 1549-1559
MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.
Nat Commun 11: 2020 4527
Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer.
Nat Commun 12: 2021 6655
Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression.
Nat Biotechnol 40: 2022 1624-1633
The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer.
Nat Cancer 4: 2023 608-628
Joint inference of exclusivity patterns and recurrent trajectories from tumor mutation trees.
Nat Commun 14: 2023 3676