title: Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes.
abstract: DNA methylation has a substantial impact on gene expression, affecting the prognosis of breast cancer (BC) patients dependent on molecular subtypes. In this study, we investigated the prognostic relevance of the expression of genes reported as aberrantly methylated, and the link between gene expression and DNA methylation in BC subtypes. The prognostic value of the expression of 144 aberrantly methylated genes was evaluated in ER+/HER2-, HER2+, and ER-/HER2- molecular BC subtypes, in a meta-analysis of two large transcriptomic cohorts of BC patients (n = 1,938 and n = 1,640). The correlation between gene expression and DNA methylation in distinct gene regions was also investigated in an independent dataset of 104 BCs. Survival and Pearson correlation analyses were computed for each gene separately. The expression of 48 genes was significantly associated with BC prognosis (p < 0.05), and 32 of these prognostic genes exhibited a direct expression-methylation correlation. The expression of several immune-related genes, including CD3D and HLA-A, was associated with both relapse-free survival (HR = 0.42, p = 3.5E-06; HR = 0.35, p = 1.7E-08) and overall survival (HR = 0.50, p = 5.5E-04; HR = 0.68, p = 4.5E-02) in ER-/HER2- BCs. On the overall, the distribution of both positive and negative expression-methylation correlation in distinct gene regions have different effects on gene expression and prognosis in BC subtypes. This large-scale meta-analysis allowed the identification of several genes consistently associated with prognosis, whose DNA methylation could represent a promising biomarker for prognostication and clinical stratification of patients with distinct BC subtypes.
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.|MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Oncology Experimental Therapeutics Unit, IRCCS Clinical and Research Institute Humanitas, Rozzano - Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bottai
authors.affiliation: Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleischer
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Munkácsy
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Oncology Experimental Therapeutics Unit, IRCCS Clinical and Research Institute Humanitas, Rozzano - Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Paladini
authors.affiliation: Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.|Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Oncology Experimental Therapeutics Unit, IRCCS Clinical and Research Institute Humanitas, Rozzano - Milan, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor
keywords: DNA methylation biomarkers; breast cancer subtypes; gene expression; immune genes; prognosis