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Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Lookup NU author(s): Dr Stella Breininger

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.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.

Publication metadata

Author(s): Izadi F, Sharpe BP, Breininger SP, Secrier M, Gibson J, Walker RC, Rahman S, Devonshire G, Lloyd MA, Walters ZS, Fitzgerald RC, Rose-Zerilli MJJ, Underwood TJ

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2021

Volume: 13

Issue: 14

Online publication date: 06/07/2021

Acceptance date: 01/07/2021

Date deposited: 06/11/2023

ISSN (electronic): 2072-6694

Publisher: MDPI

URL: https://doi.org/10.3390/cancers13143394

DOI: 10.3390/cancers13143394

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