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Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies. / Hoefnagel, Sanne J. M.; Koemans, Willem J.; Khan, Hina N. et al.

In: Cancers, Vol. 14, No. 18, 4498, 01.09.2022.

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@article{98225817f5284e13858a2d46c542bff2,
title = "Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies",
abstract = "Esophageal adenocarcinoma (EAC) is a highly aggressive cancer and its response to chemo- and radiotherapy is unpredictable. EACs are highly heterogeneous at the molecular level. The aim of this study was to perform gene expression analysis of EACs to identify distinct molecular subgroups and to investigate expression signatures in relation to treatment response. In this prospective observational study, RNA sequencing was performed on pre-treatment endoscopic EAC biopsies from a discovery cohort included between 2012 and 2017 in one Dutch Academic Center. Four additional cohorts were analyzed for validation purposes. Unsupervised clustering was performed on 107 patients to identify biological EAC subgroups. Specific cell signaling profiles were identified and evaluated with respect to predicting response to neo-adjuvant chemo(radio)therapy. We identified and validated three distinct biological EAC subgroups, characterized by (1) p38 MAPK/Toll-like receptor signaling; (2) activated immune system; and (3) impaired cell adhesion. Subgroup 1 was associated with poor response to chemo-radiotherapy. Moreover, an immune signature with activated T-cell signaling, and increased number of activated CD4 T memory cells, neutrophils and dendritic cells, and decreased M1 and M2 macrophages and plasma cells, was associated with complete histopathological response. This study provides a novel molecular classification for EACs. EAC subgroup 1 proved to be more therapy-resistant, while immune signaling was increased in patients with complete response to chemo-radiotherapy. Our findings give insight into the biology of EACs and in cellular signaling mechanisms underlying response to neo-adjuvant treatment. Future implementation of this classification will improve patient stratification and enhance the development of targeted therapies.",
keywords = "RNA sequencing, esophageal adenocarcinoma, predicting response to therapy, subgroups",
author = "Hoefnagel, {Sanne J. M.} and Koemans, {Willem J.} and Khan, {Hina N.} and Jan Koster and Meijer, {Sybren L.} and {van Dieren}, {Jolanda M.} and Kodach, {Liudmila L.} and {van Sandick}, {Johanna W.} and Silvia Calpe and {del Sancho-Serra}, {Carmen M.} and Correia, {Ana C. P.} and {van Berge Henegouwen}, {Mark I.} and Gisbertz, {Suzanne S.} and Hulshof, {Maarten C. C. M.} and Sandro Mattioli and Spaander, {Manon C. W.} and Krishnadath, {Kausilia K.}",
note = "Funding Information: This work by KKK was supported by the European Research Council (ERC) starting grant: ERC-StG 282079 TargetS4Barrett, ERC-POC 632258 BMP4EAC, and a Dutch government grant: LSH-TKI-PPP 2017. This was an investigator-initiated study. The funders had no role in the study design; in the collection, analysis or interpretation of data; in the writing of the report or in the decision to submit for publication. Publisher Copyright: {\textcopyright} 2022 by the authors.",
year = "2022",
month = sep,
day = "1",
doi = "10.3390/cancers14184498",
language = "English",
volume = "14",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "18",

}

RIS

TY - JOUR

T1 - Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies

AU - Hoefnagel, Sanne J. M.

AU - Koemans, Willem J.

AU - Khan, Hina N.

AU - Koster, Jan

AU - Meijer, Sybren L.

AU - van Dieren, Jolanda M.

AU - Kodach, Liudmila L.

AU - van Sandick, Johanna W.

AU - Calpe, Silvia

AU - del Sancho-Serra, Carmen M.

AU - Correia, Ana C. P.

AU - van Berge Henegouwen, Mark I.

AU - Gisbertz, Suzanne S.

AU - Hulshof, Maarten C. C. M.

AU - Mattioli, Sandro

AU - Spaander, Manon C. W.

AU - Krishnadath, Kausilia K.

N1 - Funding Information: This work by KKK was supported by the European Research Council (ERC) starting grant: ERC-StG 282079 TargetS4Barrett, ERC-POC 632258 BMP4EAC, and a Dutch government grant: LSH-TKI-PPP 2017. This was an investigator-initiated study. The funders had no role in the study design; in the collection, analysis or interpretation of data; in the writing of the report or in the decision to submit for publication. Publisher Copyright: © 2022 by the authors.

PY - 2022/9/1

Y1 - 2022/9/1

N2 - Esophageal adenocarcinoma (EAC) is a highly aggressive cancer and its response to chemo- and radiotherapy is unpredictable. EACs are highly heterogeneous at the molecular level. The aim of this study was to perform gene expression analysis of EACs to identify distinct molecular subgroups and to investigate expression signatures in relation to treatment response. In this prospective observational study, RNA sequencing was performed on pre-treatment endoscopic EAC biopsies from a discovery cohort included between 2012 and 2017 in one Dutch Academic Center. Four additional cohorts were analyzed for validation purposes. Unsupervised clustering was performed on 107 patients to identify biological EAC subgroups. Specific cell signaling profiles were identified and evaluated with respect to predicting response to neo-adjuvant chemo(radio)therapy. We identified and validated three distinct biological EAC subgroups, characterized by (1) p38 MAPK/Toll-like receptor signaling; (2) activated immune system; and (3) impaired cell adhesion. Subgroup 1 was associated with poor response to chemo-radiotherapy. Moreover, an immune signature with activated T-cell signaling, and increased number of activated CD4 T memory cells, neutrophils and dendritic cells, and decreased M1 and M2 macrophages and plasma cells, was associated with complete histopathological response. This study provides a novel molecular classification for EACs. EAC subgroup 1 proved to be more therapy-resistant, while immune signaling was increased in patients with complete response to chemo-radiotherapy. Our findings give insight into the biology of EACs and in cellular signaling mechanisms underlying response to neo-adjuvant treatment. Future implementation of this classification will improve patient stratification and enhance the development of targeted therapies.

AB - Esophageal adenocarcinoma (EAC) is a highly aggressive cancer and its response to chemo- and radiotherapy is unpredictable. EACs are highly heterogeneous at the molecular level. The aim of this study was to perform gene expression analysis of EACs to identify distinct molecular subgroups and to investigate expression signatures in relation to treatment response. In this prospective observational study, RNA sequencing was performed on pre-treatment endoscopic EAC biopsies from a discovery cohort included between 2012 and 2017 in one Dutch Academic Center. Four additional cohorts were analyzed for validation purposes. Unsupervised clustering was performed on 107 patients to identify biological EAC subgroups. Specific cell signaling profiles were identified and evaluated with respect to predicting response to neo-adjuvant chemo(radio)therapy. We identified and validated three distinct biological EAC subgroups, characterized by (1) p38 MAPK/Toll-like receptor signaling; (2) activated immune system; and (3) impaired cell adhesion. Subgroup 1 was associated with poor response to chemo-radiotherapy. Moreover, an immune signature with activated T-cell signaling, and increased number of activated CD4 T memory cells, neutrophils and dendritic cells, and decreased M1 and M2 macrophages and plasma cells, was associated with complete histopathological response. This study provides a novel molecular classification for EACs. EAC subgroup 1 proved to be more therapy-resistant, while immune signaling was increased in patients with complete response to chemo-radiotherapy. Our findings give insight into the biology of EACs and in cellular signaling mechanisms underlying response to neo-adjuvant treatment. Future implementation of this classification will improve patient stratification and enhance the development of targeted therapies.

KW - RNA sequencing

KW - esophageal adenocarcinoma

KW - predicting response to therapy

KW - subgroups

UR - http://www.scopus.com/inward/record.url?scp=85138701136&partnerID=8YFLogxK

U2 - 10.3390/cancers14184498

DO - 10.3390/cancers14184498

M3 - Article

C2 - 36139661

VL - 14

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 18

M1 - 4498

ER -

ID: 26296092