Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3390/cancers12113079 http://hdl.handle.net/11449/208068 |
Resumo: | The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cisregulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality. |
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Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer5-fluorouracilHigh-throughput DNA methylation analysisPredictive biomarkerTranslational researchThe treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cisregulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Estadual PaulistaCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Department of Clinical Genetics University Hospital of Southern DenmarkInternational Research Center–CIPE A.C. Camargo Cancer CenterDepartment of Head and Neck Surgery Hospital das Clinicas HCFMUSPDepartment of Chemical and Biological Sciences Institute of Biosciences Sao Paulo State University (Unesp)Institute of Biological Psychiatry Psykiatrisk Center Sct. HansColorectal Cancer Service A.C. Camargo Cancer CenterDepartment of Pathology Sírio-Libanês HospitalMolecular Oncology Research CenterDiagnósticos da América (DASA)Department of Oncology University Hospital of Southern DenmarkDanish Colorectal Cancer Center SouthDepartment of Pathology University Hospital of Southern DenmarkTUM School of Life Sciences Weihenstephan Technical University of MunichInstitute of Regional Health Research Faculty of Health Sciences University of Southern DenmarkDepartment of Chemical and Biological Sciences Institute of Biosciences Sao Paulo State University (Unesp)CNPq: #573589/08-9Universidade Estadual Paulista: 001CAPES: CAPESUniversity Hospital of Southern DenmarkA.C. Camargo Cancer CenterUniversidade de São Paulo (USP)Universidade Estadual Paulista (Unesp)Psykiatrisk Center Sct. HansSírio-Libanês HospitalMolecular Oncology Research CenterDiagnósticos da América (DASA)Danish Colorectal Cancer Center SouthTechnical University of MunichUniversity of Southern DenmarkCanto, Luisa Matos DoBarros-Filho, Mateus CamargoRainho, Cláudia Aparecida [UNESP]Marinho, DiogoKupper, Bruna Elisa CatinBegnami, Maria Dirlei Ferreira de SouzaScapulatempo-Neto, CristovamHavelund, Birgitte MaylandLindebjerg, JanMarchi, Fabio AlbuquerqueBaumbach, JanAguiar, SamuelRogatto, Silvia Regina2021-06-25T11:05:48Z2021-06-25T11:05:48Z2020-11-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1-19http://dx.doi.org/10.3390/cancers12113079Cancers, v. 12, n. 11, p. 1-19, 2020.2072-6694http://hdl.handle.net/11449/20806810.3390/cancers121130792-s2.0-8509391470088148235451595040000-0002-0285-1162Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengCancersinfo:eu-repo/semantics/openAccess2021-10-22T20:36:29Zoai:repositorio.unesp.br:11449/208068Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:10:33.821836Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
title |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
spellingShingle |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer Canto, Luisa Matos Do 5-fluorouracil High-throughput DNA methylation analysis Predictive biomarker Translational research |
title_short |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
title_full |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
title_fullStr |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
title_full_unstemmed |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
title_sort |
Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer |
author |
Canto, Luisa Matos Do |
author_facet |
Canto, Luisa Matos Do Barros-Filho, Mateus Camargo Rainho, Cláudia Aparecida [UNESP] Marinho, Diogo Kupper, Bruna Elisa Catin Begnami, Maria Dirlei Ferreira de Souza Scapulatempo-Neto, Cristovam Havelund, Birgitte Mayland Lindebjerg, Jan Marchi, Fabio Albuquerque Baumbach, Jan Aguiar, Samuel Rogatto, Silvia Regina |
author_role |
author |
author2 |
Barros-Filho, Mateus Camargo Rainho, Cláudia Aparecida [UNESP] Marinho, Diogo Kupper, Bruna Elisa Catin Begnami, Maria Dirlei Ferreira de Souza Scapulatempo-Neto, Cristovam Havelund, Birgitte Mayland Lindebjerg, Jan Marchi, Fabio Albuquerque Baumbach, Jan Aguiar, Samuel Rogatto, Silvia Regina |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
University Hospital of Southern Denmark A.C. Camargo Cancer Center Universidade de São Paulo (USP) Universidade Estadual Paulista (Unesp) Psykiatrisk Center Sct. Hans Sírio-Libanês Hospital Molecular Oncology Research Center Diagnósticos da América (DASA) Danish Colorectal Cancer Center South Technical University of Munich University of Southern Denmark |
dc.contributor.author.fl_str_mv |
Canto, Luisa Matos Do Barros-Filho, Mateus Camargo Rainho, Cláudia Aparecida [UNESP] Marinho, Diogo Kupper, Bruna Elisa Catin Begnami, Maria Dirlei Ferreira de Souza Scapulatempo-Neto, Cristovam Havelund, Birgitte Mayland Lindebjerg, Jan Marchi, Fabio Albuquerque Baumbach, Jan Aguiar, Samuel Rogatto, Silvia Regina |
dc.subject.por.fl_str_mv |
5-fluorouracil High-throughput DNA methylation analysis Predictive biomarker Translational research |
topic |
5-fluorouracil High-throughput DNA methylation analysis Predictive biomarker Translational research |
description |
The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cisregulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-11-01 2021-06-25T11:05:48Z 2021-06-25T11:05:48Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3390/cancers12113079 Cancers, v. 12, n. 11, p. 1-19, 2020. 2072-6694 http://hdl.handle.net/11449/208068 10.3390/cancers12113079 2-s2.0-85093914700 8814823545159504 0000-0002-0285-1162 |
url |
http://dx.doi.org/10.3390/cancers12113079 http://hdl.handle.net/11449/208068 |
identifier_str_mv |
Cancers, v. 12, n. 11, p. 1-19, 2020. 2072-6694 10.3390/cancers12113079 2-s2.0-85093914700 8814823545159504 0000-0002-0285-1162 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cancers |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1-19 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129293500284928 |