Tracking the Evolution of Non-Small-Cell Lung Cancer

M Jamal-Hanjani; GA Wilson; N McGranahan; NJ Birkbak; TBK Watkins; S Veeriah; S Shafi; DH Johnson; R Mitter; R Rosenthal; M Salm; S Horswell; M Escudero; N Matthews; A Rowan; T Chambers; DA Moore; S Turajlic; H Xu; SM Lee; MD Forster; T Ahmad; CT Hiley; C Abbosh; M Falzon; E Borg; T Marafioti; D Lawrence; M Hayward; S Kolvekar; N Panagiotopoulos; SM Janes; R Thakrar; A Ahmed; Fiona Blackhall; Y Summers; R Shah; L Joseph; AM Quinn; Philip Crosbie; B Naidu; G Middleton; G Langman; S Trotter; M Nicolson; H Remmen; K Kerr; M Chetty; L Gommersall; DA Fennell; A Nakas; S Rathinam; G Anand; S Khan; P Russell; V Ezhil; B Ismail; M Irvin-Sellers; V Prakash; JF Lester; M Kornaszewska; R Attanoos; H Adams; H Davies; S Dentro; P Taniere; B O'Sullivan; HL Lowe; JA Hartley; N Iles; H Bell; Y Ngai; JA Shaw; J Herrero; Z Szallasi; RF Schwarz; A Stewart; SA Quezada; J Le Quesne; P Van Loo; Caroline Dive; A. Hackshaw; C Swanton

doi:10.1056/NEJMoa1616288

Tracking the Evolution of Non-Small-Cell Lung Cancer

M Jamal-Hanjani, GA Wilson, N McGranahan, NJ Birkbak, TBK Watkins, S Veeriah, S Shafi, DH Johnson, R Mitter, R Rosenthal, M Salm, S Horswell, M Escudero, N Matthews, A Rowan, T Chambers, DA Moore, S Turajlic, H Xu, SM LeeMD Forster, T Ahmad, CT Hiley, C Abbosh, M Falzon, E Borg, T Marafioti, D Lawrence, M Hayward, S Kolvekar, N Panagiotopoulos, SM Janes, R Thakrar, A Ahmed, Fiona Blackhall, Y Summers, R Shah, L Joseph, AM Quinn, Philip Crosbie, B Naidu, G Middleton, G Langman, S Trotter, M Nicolson, H Remmen, K Kerr, M Chetty, L Gommersall, DA Fennell, A Nakas, S Rathinam, G Anand, S Khan, P Russell, V Ezhil, B Ismail, M Irvin-Sellers, V Prakash, JF Lester, M Kornaszewska, R Attanoos, H Adams, H Davies, S Dentro, P Taniere, B O'Sullivan, HL Lowe, JA Hartley, N Iles, H Bell, Y Ngai, JA Shaw, J Herrero, Z Szallasi, RF Schwarz, A Stewart, SA Quezada, J Le Quesne, P Van Loo, Caroline Dive, A. Hackshaw, C Swanton

Tracerx Consortium

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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	The New England Journal of Medicine
Volume	376
Issue number	22
Early online date	26 Apr 2017
DOIs	https://doi.org/10.1056/NEJMoa1616288 https://doi.org/10.1056/NEJMoa1616288
Publication status	Published - 1 Jun 2017

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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., ... Swanton, C. (2017). Tracking the Evolution of Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 376(22), 2109-2121. https://doi.org/10.1056/NEJMoa1616288, https://doi.org/10.1056/NEJMoa1616288

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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 = "M Jamal-Hanjani and GA Wilson and N McGranahan and NJ Birkbak and TBK Watkins and S Veeriah and S Shafi and DH Johnson and R Mitter and R Rosenthal and M Salm and S Horswell and M Escudero and N Matthews and A Rowan and T Chambers and DA Moore and S Turajlic and H Xu and SM Lee and MD Forster and T Ahmad and CT Hiley and C Abbosh and M Falzon and E Borg and T Marafioti and D Lawrence and M Hayward and S Kolvekar and N Panagiotopoulos and SM Janes and R Thakrar and A Ahmed and Fiona Blackhall and Y Summers and R Shah and L Joseph and AM Quinn and Philip Crosbie and B Naidu and G Middleton and G Langman and S Trotter and M Nicolson and H Remmen and K Kerr and M Chetty and L Gommersall and DA Fennell and A Nakas and S Rathinam and G Anand and S Khan and P Russell and V Ezhil and B Ismail and M Irvin-Sellers and V Prakash and JF Lester and M Kornaszewska and R Attanoos and H Adams and H Davies and S Dentro and P Taniere and B O'Sullivan and HL Lowe and JA Hartley and N Iles and H Bell and Y Ngai and JA Shaw and J Herrero and Z Szallasi and RF Schwarz and A Stewart and SA Quezada and {Le Quesne}, J and {Van Loo}, P and Caroline Dive and A. Hackshaw and C Swanton",

year = "2017",

month = jun,

day = "1",

doi = "10.1056/NEJMoa1616288",

language = "English",

volume = "376",

pages = "2109--2121",

journal = "The New England Journal of Medicine",

issn = "1533-4406",

publisher = "Massachussetts Medical Society",

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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, SM, 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, P, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gommersall, 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', The New England Journal of Medicine, vol. 376, no. 22, pp. 2109-2121. https://doi.org/10.1056/NEJMoa1616288, https://doi.org/10.1056/NEJMoa1616288

TY - JOUR

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

AU - Jamal-Hanjani, M

AU - Wilson, GA

AU - McGranahan, N

AU - Birkbak, NJ

AU - Watkins, TBK

AU - Veeriah, S

AU - Shafi, S

AU - Johnson, DH

AU - Mitter, R

AU - Rosenthal, R

AU - Salm, M

AU - Horswell, S

AU - Escudero, M

AU - Matthews, N

AU - Rowan, A

AU - Chambers, T

AU - Moore, DA

AU - Turajlic, S

AU - Xu, H

AU - Lee, SM

AU - Forster, MD

AU - Ahmad, T

AU - Hiley, CT

AU - Abbosh, C

AU - Falzon, M

AU - Borg, E

AU - Marafioti, T

AU - Lawrence, D

AU - Hayward, M

AU - Kolvekar, S

AU - Panagiotopoulos, N

AU - Janes, SM

AU - Thakrar, R

AU - Ahmed, A

AU - Blackhall, Fiona

AU - Summers, Y

AU - Shah, R

AU - Joseph, L

AU - Quinn, AM

AU - Crosbie, Philip

AU - Naidu, B

AU - Middleton, G

AU - Langman, G

AU - Trotter, S

AU - Nicolson, M

AU - Remmen, H

AU - Kerr, K

AU - Chetty, M

AU - Gommersall, L

AU - Fennell, DA

AU - Nakas, A

AU - Rathinam, S

AU - Anand, G

AU - Khan, S

AU - Russell, P

AU - Ezhil, V

AU - Ismail, B

AU - Irvin-Sellers, M

AU - Prakash, V

AU - Lester, JF

AU - Kornaszewska, M

AU - Attanoos, R

AU - Adams, H

AU - Davies, H

AU - Dentro, S

AU - Taniere, P

AU - O'Sullivan, B

AU - Lowe, HL

AU - Hartley, JA

AU - Iles, N

AU - Bell, H

AU - Ngai, Y

AU - Shaw, JA

AU - Herrero, J

AU - Szallasi, Z

AU - Schwarz, RF

AU - Stewart, A

AU - Quezada, SA

AU - Le Quesne, J

AU - Van Loo, P

AU - Dive, Caroline

AU - Hackshaw, A.

AU - Swanton, C

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 - 1533-4406

VL - 376

SP - 2109

EP - 2121

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

IS - 22

ER -

Tracking the Evolution of Non-Small-Cell Lung Cancer

Abstract

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