Comprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal cancer

dc.contributor.authorCanto, Luisa Matos Do
dc.contributor.authorBarros-Filho, Mateus Camargo
dc.contributor.authorRainho, Cláudia Aparecida [UNESP]
dc.contributor.authorMarinho, Diogo
dc.contributor.authorKupper, Bruna Elisa Catin
dc.contributor.authorBegnami, Maria Dirlei Ferreira de Souza
dc.contributor.authorScapulatempo-Neto, Cristovam
dc.contributor.authorHavelund, Birgitte Mayland
dc.contributor.authorLindebjerg, Jan
dc.contributor.authorMarchi, Fabio Albuquerque
dc.contributor.authorBaumbach, Jan
dc.contributor.authorAguiar, Samuel
dc.contributor.authorRogatto, Silvia Regina
dc.contributor.institutionUniversity Hospital of Southern Denmark
dc.contributor.institutionA.C. Camargo Cancer Center
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionPsykiatrisk Center Sct. Hans
dc.contributor.institutionSírio-Libanês Hospital
dc.contributor.institutionMolecular Oncology Research Center
dc.contributor.institutionDiagnósticos da América (DASA)
dc.contributor.institutionDanish Colorectal Cancer Center South
dc.contributor.institutionTechnical University of Munich
dc.contributor.institutionUniversity of Southern Denmark
dc.description.abstractThe 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.en
dc.description.affiliationDepartment of Clinical Genetics University Hospital of Southern Denmark
dc.description.affiliationInternational Research Center–CIPE A.C. Camargo Cancer Center
dc.description.affiliationDepartment of Head and Neck Surgery Hospital das Clinicas HCFMUSP
dc.description.affiliationDepartment of Chemical and Biological Sciences Institute of Biosciences Sao Paulo State University (Unesp)
dc.description.affiliationInstitute of Biological Psychiatry Psykiatrisk Center Sct. Hans
dc.description.affiliationColorectal Cancer Service A.C. Camargo Cancer Center
dc.description.affiliationDepartment of Pathology Sírio-Libanês Hospital
dc.description.affiliationMolecular Oncology Research Center
dc.description.affiliationDiagnósticos da América (DASA)
dc.description.affiliationDepartment of Oncology University Hospital of Southern Denmark
dc.description.affiliationDanish Colorectal Cancer Center South
dc.description.affiliationDepartment of Pathology University Hospital of Southern Denmark
dc.description.affiliationTUM School of Life Sciences Weihenstephan Technical University of Munich
dc.description.affiliationInstitute of Regional Health Research Faculty of Health Sciences University of Southern Denmark
dc.description.affiliationUnespDepartment of Chemical and Biological Sciences Institute of Biosciences Sao Paulo State University (Unesp)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipUniversidade Estadual Paulista
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipIdCNPq: #573589/08-9
dc.description.sponsorshipIdUniversidade Estadual Paulista: 001
dc.description.sponsorshipIdCAPES: CAPES
dc.identifier.citationCancers, v. 12, n. 11, p. 1-19, 2020.
dc.subjectHigh-throughput DNA methylation analysis
dc.subjectPredictive biomarker
dc.subjectTranslational research
dc.titleComprehensive analysis of DNA methylation and prediction of response to neoadjuvanttherapy in locally advanced rectal canceren