The evolution of lung cancer and impact of subclonal selection in TRACERx

Alexander M. Frankell; Michelle Dietzen; Maise Al Bakir; Emilia L. Lim; Takahiro Karasaki; Sophia Ward; Selvaraju Veeriah; Emma Colliver; Ariana Huebner; Abigail Bunkum; Mark S. Hill; Kristiana Grigoriadis; David A. Moore; James R.M. Black; Wing Kin Liu; Kerstin Thol; Oriol Pich; Thomas B.K. Watkins; Cristina Naceur-Lombardelli; Daniel E. Cook; Roberto Salgado; Gareth A. Wilson; Chris Bailey; Mihaela Angelova; Robert Bentham; Carlos Martínez-Ruiz; Christopher Abbosh; Andrew G. Nicholson; John Le Quesne; Dhruva Biswas; Rachel Rosenthal; Clare Puttick; Sonya Hessey; Claudia Lee; Paulina Prymas; Antonia Toncheva; Jon Smith; Wei Xing; Jerome Nicod; Gillian Price; Keith M. Kerr; Babu Naidu; Gary Middleton; Kevin G. Blyth; Dean A. Fennell; Nicolai J. Birkbak; Judit Kisistok; Mateo Sokac; TRACERx Consortium

doi:10.1038/s41586-023-05783-5

The evolution of lung cancer and impact of subclonal selection in TRACERx

Alexander M. Frankell, Michelle Dietzen, Maise Al Bakir, Emilia L. Lim, Takahiro Karasaki, Sophia Ward, Selvaraju Veeriah, Emma Colliver, Ariana Huebner, Abigail Bunkum, Mark S. Hill, Kristiana Grigoriadis, David A. Moore, James R.M. Black, Wing Kin Liu, Kerstin Thol, Oriol Pich, Thomas B.K. Watkins, Cristina Naceur-Lombardelli, Daniel E. CookRoberto Salgado, Gareth A. Wilson, Chris Bailey, Mihaela Angelova, Robert Bentham, Carlos Martínez-Ruiz, Christopher Abbosh, Andrew G. Nicholson, John Le Quesne, Dhruva Biswas, Rachel Rosenthal, Clare Puttick, Sonya Hessey, Claudia Lee, Paulina Prymas, Antonia Toncheva, Jon Smith, Wei Xing, Jerome Nicod, Gillian Price, Keith M. Kerr, Babu Naidu, Gary Middleton, Kevin G. Blyth, Dean A. Fennell, Nicolai J. Birkbak, Judit Kisistok (Member of author collaboration), Mateo Sokac, TRACERx Consortium

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

102 Citations (Scopus)

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide¹. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Original language	English
Journal	Nature
Volume	616
Issue	7957
Pages (from-to)	525-533
Number of pages	9
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-023-05783-5
Publication status	Published - Apr 2023

Keywords

Adenocarcinoma of Lung/etiology
Carcinoma, Non-Small-Cell Lung/etiology
DNA Copy Number Variations
Humans
Lung Neoplasms/etiology
Mutagenesis
Mutation
Neoplasm Recurrence, Local/genetics
Phylogeny
Smoking/genetics
Treatment Outcome

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Frankell, A. M., Dietzen, M., Al Bakir, M., Lim, E. L., Karasaki, T., Ward, S., Veeriah, S., Colliver, E., Huebner, A., Bunkum, A., Hill, M. S., Grigoriadis, K., Moore, D. A., Black, J. R. M., Liu, W. K., Thol, K., Pich, O., Watkins, T. B. K., Naceur-Lombardelli, C., ... TRACERx Consortium (2023). The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature, 616(7957), 525-533. https://doi.org/10.1038/s41586-023-05783-5

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title = "The evolution of lung cancer and impact of subclonal selection in TRACERx",

abstract = "Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.",

keywords = "Adenocarcinoma of Lung/etiology, Carcinoma, Non-Small-Cell Lung/etiology, DNA Copy Number Variations, Humans, Lung Neoplasms/etiology, Mutagenesis, Mutation, Neoplasm Recurrence, Local/genetics, Phylogeny, Smoking/genetics, Treatment Outcome",

author = "Frankell, {Alexander M.} and Michelle Dietzen and {Al Bakir}, Maise and Lim, {Emilia L.} and Takahiro Karasaki and Sophia Ward and Selvaraju Veeriah and Emma Colliver and Ariana Huebner and Abigail Bunkum and Hill, {Mark S.} and Kristiana Grigoriadis and Moore, {David A.} and Black, {James R.M.} and Liu, {Wing Kin} and Kerstin Thol and Oriol Pich and Watkins, {Thomas B.K.} and Cristina Naceur-Lombardelli and Cook, {Daniel E.} and Roberto Salgado and Wilson, {Gareth A.} and Chris Bailey and Mihaela Angelova and Robert Bentham and Carlos Mart{\'i}nez-Ruiz and Christopher Abbosh and Nicholson, {Andrew G.} and {Le Quesne}, John and Dhruva Biswas and Rachel Rosenthal and Clare Puttick and Sonya Hessey and Claudia Lee and Paulina Prymas and Antonia Toncheva and Jon Smith and Wei Xing and Jerome Nicod and Gillian Price and Kerr, {Keith M.} and Babu Naidu and Gary Middleton and Blyth, {Kevin G.} and Fennell, {Dean A.} and Birkbak, {Nicolai J.} and Judit Kisistok and Mateo Sokac and {TRACERx Consortium}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = apr,

doi = "10.1038/s41586-023-05783-5",

language = "English",

volume = "616",

pages = "525--533",

journal = "Nature",

issn = "0028-0836",

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Frankell, AM, Dietzen, M, Al Bakir, M, Lim, EL, Karasaki, T, Ward, S, Veeriah, S, Colliver, E, Huebner, A, Bunkum, A, Hill, MS, Grigoriadis, K, Moore, DA, Black, JRM, Liu, WK, Thol, K, Pich, O, Watkins, TBK, Naceur-Lombardelli, C, Cook, DE, Salgado, R, Wilson, GA, Bailey, C, Angelova, M, Bentham, R, Martínez-Ruiz, C, Abbosh, C, Nicholson, AG, Le Quesne, J, Biswas, D, Rosenthal, R, Puttick, C, Hessey, S, Lee, C, Prymas, P, Toncheva, A, Smith, J, Xing, W, Nicod, J, Price, G, Kerr, KM, Naidu, B, Middleton, G, Blyth, KG, Fennell, DA, Birkbak, NJ , Kisistok, J, Sokac, M & TRACERx Consortium 2023, 'The evolution of lung cancer and impact of subclonal selection in TRACERx', Nature, vol. 616, no. 7957, pp. 525-533. https://doi.org/10.1038/s41586-023-05783-5

TY - JOUR

T1 - The evolution of lung cancer and impact of subclonal selection in TRACERx

AU - Frankell, Alexander M.

AU - Dietzen, Michelle

AU - Al Bakir, Maise

AU - Lim, Emilia L.

AU - Karasaki, Takahiro

AU - Ward, Sophia

AU - Veeriah, Selvaraju

AU - Colliver, Emma

AU - Huebner, Ariana

AU - Bunkum, Abigail

AU - Hill, Mark S.

AU - Grigoriadis, Kristiana

AU - Moore, David A.

AU - Black, James R.M.

AU - Liu, Wing Kin

AU - Thol, Kerstin

AU - Pich, Oriol

AU - Watkins, Thomas B.K.

AU - Naceur-Lombardelli, Cristina

AU - Cook, Daniel E.

AU - Salgado, Roberto

AU - Wilson, Gareth A.

AU - Bailey, Chris

AU - Angelova, Mihaela

AU - Bentham, Robert

AU - Martínez-Ruiz, Carlos

AU - Abbosh, Christopher

AU - Nicholson, Andrew G.

AU - Le Quesne, John

AU - Biswas, Dhruva

AU - Rosenthal, Rachel

AU - Puttick, Clare

AU - Hessey, Sonya

AU - Lee, Claudia

AU - Prymas, Paulina

AU - Toncheva, Antonia

AU - Smith, Jon

AU - Xing, Wei

AU - Nicod, Jerome

AU - Price, Gillian

AU - Kerr, Keith M.

AU - Naidu, Babu

AU - Middleton, Gary

AU - Blyth, Kevin G.

AU - Fennell, Dean A.

AU - Birkbak, Nicolai J.

AU - Kisistok, Judit

AU - Sokac, Mateo

AU - TRACERx Consortium

PY - 2023/4

Y1 - 2023/4

N2 - Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

AB - Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

KW - Adenocarcinoma of Lung/etiology

KW - Carcinoma, Non-Small-Cell Lung/etiology

KW - DNA Copy Number Variations

KW - Humans

KW - Lung Neoplasms/etiology

KW - Mutagenesis

KW - Mutation

KW - Neoplasm Recurrence, Local/genetics

KW - Phylogeny

KW - Smoking/genetics

KW - Treatment Outcome

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U2 - 10.1038/s41586-023-05783-5

DO - 10.1038/s41586-023-05783-5

M3 - Journal article

C2 - 37046096

AN - SCOPUS:85152360902

SN - 0028-0836

VL - 616

SP - 525

EP - 533

JO - Nature

JF - Nature

IS - 7957

ER -

The evolution of lung cancer and impact of subclonal selection in TRACERx

Abstract

Keywords

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