Tracking the Evolution of Non-Small-Cell Lung Cancer

Mariam Jamal-hanjani; Gareth A. Wilson; Nicholas Mcgranahan; Nicolai J. Birkbak; Thomas B.k. Watkins; Selvaraju Veeriah; Seema Shafi; Diana H. Johnson; Richard Mitter; Rachel Rosenthal; Max Salm; Stuart Horswell; Mickael Escudero; Nik Matthews; Andrew Rowan; Tim Chambers; David A. Moore; Samra Turajlic; Hang Xu; Siow-ming Lee; Martin D. Forster; Tanya Ahmad; Crispin T. Hiley; Christopher Abbosh; Mary Falzon; Elaine Borg; Teresa Marafioti; David Lawrence; Martin Hayward; Shyam Kolvekar; Nikolaos Panagiotopoulos; Sam M. Janes; Ricky Thakrar; Asia Ahmed; Fiona Blackhall; Yvonne Summers; Rajesh Shah; Leena Joseph; Anne M. Quinn; Phil A. Crosbie; Babu Naidu; Gary Middleton; Gerald Langman; Simon Trotter; Marianne Nicolson; Hardy Remmen; Keith Kerr; Mahendran Chetty; Lesley Gomersall; Dean A. Fennell; Apostolos Nakas; Sridhar Rathinam; Girija Anand; Sajid Khan; Peter Russell; Veni Ezhil; Babikir Ismail; Melanie Irvin-sellers; Vineet Prakash; Jason F. Lester; Malgorzata Kornaszewska; Richard Attanoos; Haydn Adams; Helen Davies; Stefan Dentro; Philippe Taniere; Brendan O?sullivan; Helen L. Lowe; John A. Hartley; Natasha Iles; Harriet Bell; Yenting Ngai; Jacqui A. Shaw; Javier Herrero; Zoltan Szallasi; Roland F. Schwarz; Aengus Stewart; Sergio A. Quezada; John Le Quesne; Peter Van Loo; Caroline Dive; Allan Hackshaw; Charles Swanton

doi:10.1056/NEJMoa1616288

Tracking the Evolution of Non-Small-Cell Lung Cancer

Mariam Jamal-hanjani, Gareth A. Wilson, Nicholas Mcgranahan, Nicolai J. Birkbak, Thomas B.k. Watkins, Selvaraju Veeriah, Seema Shafi, Diana H. Johnson, Richard Mitter, Rachel Rosenthal, Max Salm, Stuart Horswell, Mickael Escudero, Nik Matthews, Andrew Rowan, Tim Chambers, David A. Moore, Samra Turajlic, Hang Xu, Siow-ming LeeMartin D. Forster, Tanya Ahmad, Crispin T. Hiley, Christopher Abbosh, Mary Falzon, Elaine Borg, Teresa Marafioti, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M. Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Rajesh Shah, Leena Joseph, Anne M. Quinn, Phil A. Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A. Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-sellers, Vineet Prakash, Jason F. Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Stefan Dentro, Philippe Taniere, Brendan O?sullivan, Helen L. Lowe, John A. Hartley, Natasha Iles, Harriet Bell, Yenting Ngai, Jacqui A. Shaw, Javier Herrero, Zoltan Szallasi, Roland F. Schwarz, Aengus Stewart, Sergio A. Quezada, John Le Quesne, Peter Van Loo, Caroline Dive, Allan Hackshaw, Charles Swanton

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Abstract

BACKGROUND:
Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.
METHODS:
In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.
RESULTS:
We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis.
CONCLUSIONS:
Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Original language	English
Pages (from-to)	2109-2121
Journal	New England Journal of Medicine
Volume	376
Issue number	22
Early online date	26 Apr 2017
DOIs	https://doi.org/10.1056/NEJMoa1616288
Publication status	Published - 1 Jun 2017

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10.1056/NEJMoa1616288

Hanjani_et_al_Tracking_Evolution_NEJM
Published as detailed above in the New England Journal of Medicine. © 2017 Massachusetts Medical Society. Checked 22/6/2017
Final published version, 937 KBLicence: None: All rights reserved

Cite this

Jamal-hanjani, M., Wilson, G. A., Mcgranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., Shafi, S., Johnson, D. H., Mitter, R., Rosenthal, R., Salm, M., Horswell, S., Escudero, M., Matthews, N., Rowan, A., Chambers, T., Moore, D. A., Turajlic, S., Xu, H., ... Swanton, C. (2017). Tracking the Evolution of Non-Small-Cell Lung Cancer. New England Journal of Medicine, 376(22), 2109-2121. https://doi.org/10.1056/NEJMoa1616288

@article{cdec88369df5439e99c82cfbbf636f79,

title = "Tracking the Evolution of Non-Small-Cell Lung Cancer",

abstract = "BACKGROUND:Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.METHODS:In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.RESULTS:We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis.CONCLUSIONS:Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).",

author = "Mariam Jamal-hanjani and Wilson, {Gareth A.} and Nicholas Mcgranahan and Birkbak, {Nicolai J.} and Watkins, {Thomas B.k.} and Selvaraju Veeriah and Seema Shafi and Johnson, {Diana H.} and Richard Mitter and Rachel Rosenthal and Max Salm and Stuart Horswell and Mickael Escudero and Nik Matthews and Andrew Rowan and Tim Chambers and Moore, {David A.} and Samra Turajlic and Hang Xu and Siow-ming Lee and Forster, {Martin D.} and Tanya Ahmad and Hiley, {Crispin T.} and Christopher Abbosh and Mary Falzon and Elaine Borg and Teresa Marafioti and David Lawrence and Martin Hayward and Shyam Kolvekar and Nikolaos Panagiotopoulos and Janes, {Sam M.} and Ricky Thakrar and Asia Ahmed and Fiona Blackhall and Yvonne Summers and Rajesh Shah and Leena Joseph and Quinn, {Anne M.} and Crosbie, {Phil A.} and Babu Naidu and Gary Middleton and Gerald Langman and Simon Trotter and Marianne Nicolson and Hardy Remmen and Keith Kerr and Mahendran Chetty and Lesley Gomersall and Fennell, {Dean A.} and Apostolos Nakas and Sridhar Rathinam and Girija Anand and Sajid Khan and Peter Russell and Veni Ezhil and Babikir Ismail and Melanie Irvin-sellers and Vineet Prakash and Lester, {Jason F.} and Malgorzata Kornaszewska and Richard Attanoos and Haydn Adams and Helen Davies and Stefan Dentro and Philippe Taniere and Brendan O?sullivan and Lowe, {Helen L.} and Hartley, {John A.} and Natasha Iles and Harriet Bell and Yenting Ngai and Shaw, {Jacqui A.} and Javier Herrero and Zoltan Szallasi and Schwarz, {Roland F.} and Aengus Stewart and Quezada, {Sergio A.} and {Le Quesne}, John and {Van Loo}, Peter and Caroline Dive and Allan Hackshaw and Charles Swanton",

year = "2017",

month = jun,

day = "1",

doi = "10.1056/NEJMoa1616288",

language = "English",

volume = "376",

pages = "2109--2121",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "22",

}

Jamal-hanjani, M, Wilson, GA, Mcgranahan, N, Birkbak, NJ, Watkins, TBK, Veeriah, S, Shafi, S, Johnson, DH, Mitter, R, Rosenthal, R, Salm, M, Horswell, S, Escudero, M, Matthews, N, Rowan, A, Chambers, T, Moore, DA, Turajlic, S, Xu, H, Lee, S, Forster, MD, Ahmad, T, Hiley, CT, Abbosh, C, Falzon, M, Borg, E, Marafioti, T, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Shah, R, Joseph, L, Quinn, AM, 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, Dentro, S, Taniere, P, O?sullivan, B, Lowe, HL, Hartley, JA, Iles, N, Bell, H, Ngai, Y, Shaw, JA, Herrero, J, Szallasi, Z, Schwarz, RF, Stewart, A, Quezada, SA, Le Quesne, J, Van Loo, P, Dive, C, Hackshaw, A & Swanton, C 2017, 'Tracking the Evolution of Non-Small-Cell Lung Cancer', New England Journal of Medicine, vol. 376, no. 22, pp. 2109-2121. https://doi.org/10.1056/NEJMoa1616288

TY - JOUR

T1 - Tracking the Evolution of Non-Small-Cell Lung Cancer

AU - Jamal-hanjani, Mariam

AU - Wilson, Gareth A.

AU - Mcgranahan, Nicholas

AU - Birkbak, Nicolai J.

AU - Watkins, Thomas B.k.

AU - Veeriah, Selvaraju

AU - Shafi, Seema

AU - Johnson, Diana H.

AU - Mitter, Richard

AU - Rosenthal, Rachel

AU - Salm, Max

AU - Horswell, Stuart

AU - Escudero, Mickael

AU - Matthews, Nik

AU - Rowan, Andrew

AU - Chambers, Tim

AU - Moore, David A.

AU - Turajlic, Samra

AU - Xu, Hang

AU - Lee, Siow-ming

AU - Forster, Martin D.

AU - Ahmad, Tanya

AU - Hiley, Crispin T.

AU - Abbosh, Christopher

AU - Falzon, Mary

AU - Borg, Elaine

AU - Marafioti, Teresa

AU - Lawrence, David

AU - Hayward, Martin

AU - Kolvekar, Shyam

AU - Panagiotopoulos, Nikolaos

AU - Janes, Sam M.

AU - Thakrar, Ricky

AU - Ahmed, Asia

AU - Blackhall, Fiona

AU - Summers, Yvonne

AU - Shah, Rajesh

AU - Joseph, Leena

AU - Quinn, Anne M.

AU - Crosbie, Phil A.

AU - Naidu, Babu

AU - Middleton, Gary

AU - Langman, Gerald

AU - Trotter, Simon

AU - Nicolson, Marianne

AU - Remmen, Hardy

AU - Kerr, Keith

AU - Chetty, Mahendran

AU - Gomersall, Lesley

AU - Fennell, Dean A.

AU - Nakas, Apostolos

AU - Rathinam, Sridhar

AU - Anand, Girija

AU - Khan, Sajid

AU - Russell, Peter

AU - Ezhil, Veni

AU - Ismail, Babikir

AU - Irvin-sellers, Melanie

AU - Prakash, Vineet

AU - Lester, Jason F.

AU - Kornaszewska, Malgorzata

AU - Attanoos, Richard

AU - Adams, Haydn

AU - Davies, Helen

AU - Dentro, Stefan

AU - Taniere, Philippe

AU - O?sullivan, Brendan

AU - Lowe, Helen L.

AU - Hartley, John A.

AU - Iles, Natasha

AU - Bell, Harriet

AU - Ngai, Yenting

AU - Shaw, Jacqui A.

AU - Herrero, Javier

AU - Szallasi, Zoltan

AU - Schwarz, Roland F.

AU - Stewart, Aengus

AU - Quezada, Sergio A.

AU - Le Quesne, John

AU - Van Loo, Peter

AU - Dive, Caroline

AU - Hackshaw, Allan

AU - Swanton, Charles

PY - 2017/6/1

Y1 - 2017/6/1

N2 - BACKGROUND:Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.METHODS:In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.RESULTS:We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis.CONCLUSIONS:Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

AB - BACKGROUND:Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.METHODS:In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.RESULTS:We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis.CONCLUSIONS:Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

U2 - 10.1056/NEJMoa1616288

DO - 10.1056/NEJMoa1616288

M3 - Article

SN - 0028-4793

VL - 376

SP - 2109

EP - 2121

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 22

ER -

Tracking the Evolution of Non-Small-Cell Lung Cancer

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