DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial

Raghav Sundar; Alvin Ng; Hermioni Zouridis; Nisha Padmanabhan; Taotao Sheng; Shenli Zhang; Ming Hui Lee; Wen Fong Ooi; Aditi Qamra; Imran Inam; Lindsay C. Hewitt; Jimmy Bok-Yan So; Vivien Koh; Matthew G. Nankivell; Ruth E. Langley; William H. Allum; David Cunningham; Steven G. Rozen; Wei Peng Yong; Heike I. Grabsch; Patrick Tan

doi:10.1016/j.ejca.2019.09.016

DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial

Raghav Sundar, Alvin Ng, Hermioni Zouridis, Nisha Padmanabhan, Taotao Sheng, Shenli Zhang, Ming Hui Lee, Wen Fong Ooi, Aditi Qamra, Imran Inam, Lindsay C. Hewitt, Jimmy Bok-Yan So, Vivien Koh, Matthew G. Nankivell, Ruth E. Langley, William H. Allum, David Cunningham, Steven G. Rozen, Wei Peng Yong, Heike I. Grabsch^*Patrick Tan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).

Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.

Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.

Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)

Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	48-57
Number of pages	10
Journal	European Journal of Cancer
Volume	123
DOIs	https://doi.org/10.1016/j.ejca.2019.09.016
Publication status	Published - Dec 2019

Keywords

Epigenetic signature
DNA methylation
Predictive biomarker
Chemotherapy
Oesophageal adenocarcinoma
GASTRIC-CANCER
OPEN-LABEL
PERIOPERATIVE CHEMOTHERAPY
METHYLATION
CAPECITABINE
RESECTION
SURGERY

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Sundar, R., Ng, A., Zouridis, H., Padmanabhan, N., Sheng, T., Zhang, S., Lee, M. H., Ooi, W. F., Qamra, A., Inam, I., Hewitt, L. C., So, J. B.-Y., Koh, V., Nankivell, M. G., Langley, R. E., Allum, W. H., Cunningham, D., Rozen, S. G., Yong, W. P., ... Tan, P. (2019). DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial. European Journal of Cancer, 123, 48-57. https://doi.org/10.1016/j.ejca.2019.09.016

@article{cb6fad8a4f0644a9985b9bbb2b910442,

title = "DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial",

abstract = "Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.",

keywords = "Epigenetic signature, DNA methylation, Predictive biomarker, Chemotherapy, Oesophageal adenocarcinoma, GASTRIC-CANCER, OPEN-LABEL, PERIOPERATIVE CHEMOTHERAPY, METHYLATION, CAPECITABINE, RESECTION, SURGERY",

author = "Raghav Sundar and Alvin Ng and Hermioni Zouridis and Nisha Padmanabhan and Taotao Sheng and Shenli Zhang and Lee, {Ming Hui} and Ooi, {Wen Fong} and Aditi Qamra and Imran Inam and Hewitt, {Lindsay C.} and So, {Jimmy Bok-Yan} and Vivien Koh and Nankivell, {Matthew G.} and Langley, {Ruth E.} and Allum, {William H.} and David Cunningham and Rozen, {Steven G.} and Yong, {Wei Peng} and Grabsch, {Heike I.} and Patrick Tan",

note = "Funding Information: R.S. is supported by a National Medical Research Council (NMRC) Fellowship, Singapore. P.T. is supported by Duke-NUS Medical School and the Biomedical Research Council, Agency for Science, Technology and Research . Sample collection and DNA extraction was supported by Cancer Research UK ( C26441 / A8944 , PI: H.I.G.). This work was also supported by the National Medical Research Council (grants: TCR/009-NUHS/2013 , NR13NMR111OM and NMRC/STaR/0026/2015 ). D.C. and W.H.A. acknowledge the funding support of the NIHR RM/ICR BRC ( National Institute for Health Research Royal Marsden Hospital / Institute of Cancer Research Biomedical Research Centre ). Funding Information: R.S. is supported by a National Medical Research Council (NMRC) Fellowship, Singapore. P.T. is supported by Duke-NUS Medical School and the Biomedical Research Council, Agency for Science, Technology and Research. Sample collection and DNA extraction was supported by Cancer Research UK (C26441/A8944, PI: H.I.G.). This work was also supported by the National Medical Research Council (grants: TCR/009-NUHS/2013, NR13NMR111OM and NMRC/STaR/0026/2015). D.C. and W.H.A. acknowledge the funding support of the NIHR RM/ICR BRC (National Institute for Health Research Royal Marsden Hospital/Institute of Cancer Research Biomedical Research Centre). Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = dec,

doi = "10.1016/j.ejca.2019.09.016",

language = "English",

volume = "123",

pages = "48--57",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

Sundar, R, Ng, A, Zouridis, H, Padmanabhan, N, Sheng, T, Zhang, S, Lee, MH, Ooi, WF, Qamra, A, Inam, I, Hewitt, LC, So, JB-Y, Koh, V, Nankivell, MG, Langley, RE, Allum, WH, Cunningham, D, Rozen, SG, Yong, WP, Grabsch, HI & Tan, P 2019, 'DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial', European Journal of Cancer, vol. 123, pp. 48-57. https://doi.org/10.1016/j.ejca.2019.09.016

TY - JOUR

T1 - DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma

T2 - results from the MRC OE02 trial

AU - Sundar, Raghav

AU - Ng, Alvin

AU - Zouridis, Hermioni

AU - Padmanabhan, Nisha

AU - Sheng, Taotao

AU - Zhang, Shenli

AU - Lee, Ming Hui

AU - Ooi, Wen Fong

AU - Qamra, Aditi

AU - Inam, Imran

AU - Hewitt, Lindsay C.

AU - So, Jimmy Bok-Yan

AU - Koh, Vivien

AU - Nankivell, Matthew G.

AU - Langley, Ruth E.

AU - Allum, William H.

AU - Cunningham, David

AU - Rozen, Steven G.

AU - Yong, Wei Peng

AU - Grabsch, Heike I.

AU - Tan, Patrick

N1 - Funding Information: R.S. is supported by a National Medical Research Council (NMRC) Fellowship, Singapore. P.T. is supported by Duke-NUS Medical School and the Biomedical Research Council, Agency for Science, Technology and Research . Sample collection and DNA extraction was supported by Cancer Research UK ( C26441 / A8944 , PI: H.I.G.). This work was also supported by the National Medical Research Council (grants: TCR/009-NUHS/2013 , NR13NMR111OM and NMRC/STaR/0026/2015 ). D.C. and W.H.A. acknowledge the funding support of the NIHR RM/ICR BRC ( National Institute for Health Research Royal Marsden Hospital / Institute of Cancer Research Biomedical Research Centre ). Funding Information: R.S. is supported by a National Medical Research Council (NMRC) Fellowship, Singapore. P.T. is supported by Duke-NUS Medical School and the Biomedical Research Council, Agency for Science, Technology and Research. Sample collection and DNA extraction was supported by Cancer Research UK (C26441/A8944, PI: H.I.G.). This work was also supported by the National Medical Research Council (grants: TCR/009-NUHS/2013, NR13NMR111OM and NMRC/STaR/0026/2015). D.C. and W.H.A. acknowledge the funding support of the NIHR RM/ICR BRC (National Institute for Health Research Royal Marsden Hospital/Institute of Cancer Research Biomedical Research Centre). Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/12

Y1 - 2019/12

N2 - Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.

AB - Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.

KW - Epigenetic signature

KW - DNA methylation

KW - Predictive biomarker

KW - Chemotherapy

KW - Oesophageal adenocarcinoma

KW - GASTRIC-CANCER

KW - OPEN-LABEL

KW - PERIOPERATIVE CHEMOTHERAPY

KW - METHYLATION

KW - CAPECITABINE

KW - RESECTION

KW - SURGERY

U2 - 10.1016/j.ejca.2019.09.016

DO - 10.1016/j.ejca.2019.09.016

M3 - Article

C2 - 31655359

SN - 0959-8049

VL - 123

SP - 48

EP - 57

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial

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Keywords

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