Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma
Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma
Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
Chemotherapy, Esophageal adenocarcinoma, Genomics, Mutation, NAV3, Response
Izadi, Fereshteh
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Sharpe, Benjamin P.
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Breininger, Stella P.
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Secrier, Maria
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Gibson, Jane
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Walker, Robert C.
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Rahman, Saqib
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Devonshire, Ginny
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Lloyd, Megan A.
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Walters, Zoë S.
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Fitzgerald, Rebecca C.
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Rose-Zerilli, Matthew J.J.
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Underwood, Tim J.
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6 July 2021
Izadi, Fereshteh
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Sharpe, Benjamin P.
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Breininger, Stella P.
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Secrier, Maria
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Gibson, Jane
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Walker, Robert C.
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Rahman, Saqib
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Devonshire, Ginny
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Lloyd, Megan A.
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Walters, Zoë S.
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Fitzgerald, Rebecca C.
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Rose-Zerilli, Matthew J.J.
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Underwood, Tim J.
8e81bf60-edd2-4b0e-8324-3068c95ea1c6
Izadi, Fereshteh, Sharpe, Benjamin P., Breininger, Stella P., Secrier, Maria, Gibson, Jane, Walker, Robert C., Rahman, Saqib, Devonshire, Ginny, Lloyd, Megan A., Walters, Zoë S., Fitzgerald, Rebecca C., Rose-Zerilli, Matthew J.J. and Underwood, Tim J.
,
OCCAMS
(2021)
Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma.
Cancers, 13 (14), [3394].
(doi:10.3390/cancers13143394).
Abstract
Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
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cancers-13-03394-v2
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Accepted/In Press date: 1 July 2021
Published date: 6 July 2021
Additional Information:
Funding Information:
Funding: This work was supported by Cancer Research UK & Royal College of Surgeons of England Advanced Clinician Scientist Fellowship to T.J.U. “Cellular interplay in oesophageal cancer.” A23924. M.J.R.Z was supported by the Wessex Medical Research Innovation Fund 2011 R06 and 2014 U10, Leuka Charity, John Goldman Fellowship 2016/JGF/0003 and the Southampton CRUK Centre Development Fund. Sample sequencing was funded through the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium as part of the International Cancer Genome Consortium, and was funded by a Programme Grant from Cancer Research UK (RG66287). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
This work was supported by Cancer Research UK & Royal College of Surgeons of England Advanced Clinician Scientist Fellowship to T.J.U. ?Cellular interplay in oesophageal cancer.? A23924. M.J.R.Z was supported by the Wessex Medical Research Innovation Fund 2011 R06 and 2014 U10, Leuka Charity, John Goldman Fellowship 2016/JGF/0003 and the Southampton CRUK Centre Development Fund. Sample sequencing was funded through the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium as part of the International Cancer Genome Consortium, and was funded by a Programme Grant from Cancer Research UK (RG66287). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
Keywords:
Chemotherapy, Esophageal adenocarcinoma, Genomics, Mutation, NAV3, Response
Identifiers
Local EPrints ID: 450998
URI: http://eprints.soton.ac.uk/id/eprint/450998
ISSN: 2072-6694
PURE UUID: eb352869-e75b-4a52-912f-0b22bc89b5fd
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Date deposited: 01 Sep 2021 16:31
Last modified: 18 Mar 2024 03:43
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Contributors
Author:
Fereshteh Izadi
Author:
Benjamin P. Sharpe
Author:
Stella P. Breininger
Author:
Maria Secrier
Author:
Robert C. Walker
Author:
Saqib Rahman
Author:
Ginny Devonshire
Author:
Megan A. Lloyd
Author:
Rebecca C. Fitzgerald
Corporate Author: OCCAMS
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