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Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis

Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%–15% are complete responders. Reliable selection markers would allow the identi...

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Autores principales: Croner, Roland S., Sevim, Müzeyyen, Metodiev, Metodi V., Jo, Peter, Ghadimi, Michael, Schellerer, Vera, Brunner, Maximillian, Geppert, Carol, Rau, Tilman, Stürzl, Michael, Naschberger, Elisabeth, Matzel, Klaus E., Hohenberger, Werner, Lottspeich, Friedrich, Kellermann, Josef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783941/
https://www.ncbi.nlm.nih.gov/pubmed/26861291
http://dx.doi.org/10.3390/ijms17020209
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author Croner, Roland S.
Sevim, Müzeyyen
Metodiev, Metodi V.
Jo, Peter
Ghadimi, Michael
Schellerer, Vera
Brunner, Maximillian
Geppert, Carol
Rau, Tilman
Stürzl, Michael
Naschberger, Elisabeth
Matzel, Klaus E.
Hohenberger, Werner
Lottspeich, Friedrich
Kellermann, Josef
author_facet Croner, Roland S.
Sevim, Müzeyyen
Metodiev, Metodi V.
Jo, Peter
Ghadimi, Michael
Schellerer, Vera
Brunner, Maximillian
Geppert, Carol
Rau, Tilman
Stürzl, Michael
Naschberger, Elisabeth
Matzel, Klaus E.
Hohenberger, Werner
Lottspeich, Friedrich
Kellermann, Josef
author_sort Croner, Roland S.
collection PubMed
description Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%–15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients’ informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.
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spelling pubmed-47839412016-03-14 Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis Croner, Roland S. Sevim, Müzeyyen Metodiev, Metodi V. Jo, Peter Ghadimi, Michael Schellerer, Vera Brunner, Maximillian Geppert, Carol Rau, Tilman Stürzl, Michael Naschberger, Elisabeth Matzel, Klaus E. Hohenberger, Werner Lottspeich, Friedrich Kellermann, Josef Int J Mol Sci Article Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%–15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients’ informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort. MDPI 2016-02-04 /pmc/articles/PMC4783941/ /pubmed/26861291 http://dx.doi.org/10.3390/ijms17020209 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Croner, Roland S.
Sevim, Müzeyyen
Metodiev, Metodi V.
Jo, Peter
Ghadimi, Michael
Schellerer, Vera
Brunner, Maximillian
Geppert, Carol
Rau, Tilman
Stürzl, Michael
Naschberger, Elisabeth
Matzel, Klaus E.
Hohenberger, Werner
Lottspeich, Friedrich
Kellermann, Josef
Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title_full Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title_fullStr Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title_full_unstemmed Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title_short Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
title_sort identification of predictive markers for response to neoadjuvant chemoradiation in rectal carcinomas by proteomic isotope coded protein label (icpl) analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783941/
https://www.ncbi.nlm.nih.gov/pubmed/26861291
http://dx.doi.org/10.3390/ijms17020209
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