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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 10 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001003206	BACKGROUND TRACERx (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). METHODS Multiregion 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). RESULTS Widespread 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. CONCLUSIONS ITH 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.		427

Publications	Citations
Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Grönroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG, TRACERx consortium, PEACE consortium, Swanton C. Nature 545: 2017 446-451	790
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, Birkbak NJ, Veeriah S, Van Loo P, Herrero J, Swanton C, TRACERx Consortium. Cell 171: 2017 1259-1271.e11	614
Genomic instability in mutant p53 cancer cells upon entotic engulfment. Mackay HL, Moore D, Hall C, Birkbak NJ, Jamal-Hanjani M, Karim SA, Phatak VM, Piñon L, Morton JP, Swanton C, Le Quesne J, Muller PAJ. Nat Commun 9: 2018 3070	52
A functional genetic screen defines the AKT-induced senescence signaling network. Chan KT, Blake S, Zhu H, Kang J, Trigos AS, Madhamshettiwar PB, Diesch J, Paavolainen L, Horvath P, Hannan RD, George AJ, Sanij E, Hannan KM, Simpson KJ, Pearson RB. Cell Death Differ 27: 2020 725-741	26
Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Joshi K, de Massy MR, Ismail M, Reading JL, Uddin I, Woolston A, Hatipoglu E, Oakes T, Rosenthal R, Peacock T, Ronel T, Noursadeghi M, Turati V, Furness AJS, Georgiou A, Wong YNS, Ben Aissa A, Sunderland MW, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Hiley CT, Ghorani E, Guerra-Assunção JA, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Swanton C, TRACERx consortium, Quezada SA, Chain B. Nat Med 25: 2019 1549-1559	93
MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. Munkhbaatar E, Dietzen M, Agrawal D, Anton M, Jesinghaus M, Boxberg M, Pfarr N, Bidola P, Uhrig S, Höckendorf U, Meinhardt AL, Wahida A, Heid I, Braren R, Mishra R, Warth A, Muley T, Poh PSP, Wang X, Fröhling S, Steiger K, Slotta-Huspenina J, van Griensven M, Pfeiffer F, Lange S, Rad R, Spella M, Stathopoulos GT, Ruland J, Bassermann F, Weichert W, Strasser A, Branca C, Heikenwalder M, Swanton C, McGranahan N, Jost PJ. Nat Commun 11: 2020 4527	24
Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer. Chen M, Chen R, Jin Y, Li J, Hu X, Zhang J, Fujimoto J, Hubert SM, Gay CM, Zhu B, Tian Y, McGranahan N, Lee WC, George J, Hu X, Chen Y, Wu M, Behrens C, Chow CW, Pham HHN, Fukuoka J, Wu J, Parra ER, Little LD, Gumbs C, Song X, Wu CJ, Diao L, Wang Q, Cardnell R, Zhang J, Wang J, Le X, Gibbons DL, Heymach JV, Jack Lee J, William WN, Cheng C, Glisson B, Wistuba I, Andrew Futreal P, Thomas RK, Reuben A, Byers LA, Zhang J. Nat Commun 12: 2021 6655	16
Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression. Cao S, Wang JR, Ji S, Yang P, Dai Y, Guo S, Montierth MD, Shen JP, Zhao X, Chen J, Lee JJ, Guerrero PA, Spetsieris N, Engedal N, Taavitsainen S, Yu K, Livingstone J, Bhandari V, Hubert SM, Daw NC, Futreal PA, Efstathiou E, Lim B, Viale A, Zhang J, Nykter M, Czerniak BA, Brown PH, Swanton C, Msaouel P, Maitra A, Kopetz S, Campbell P, Speed TP, Boutros PC, Zhu H, Urbanucci A, Demeulemeester J, Van Loo P, Wang W. Nat Biotechnol 40: 2022 1624-1633	23
The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer. Kraemer AI, Chong C, Huber F, Pak H, Stevenson BJ, Müller M, Michaux J, Altimiras ER, Rusakiewicz S, Simó-Riudalbas L, Planet E, Wiznerowicz M, Dagher J, Trono D, Coukos G, Tissot S, Bassani-Sternberg M. Nat Cancer 4: 2023 608-628	10
Joint inference of exclusivity patterns and recurrent trajectories from tumor mutation trees. Luo XG, Kuipers J, Beerenwinkel N. Nat Commun 14: 2023 3676	3