title: Integrated analysis of high-resolution DNA methylation profiles, gene expression, germline genotypes and clinical end points in breast cancer patients.
abstract: Breast cancer is a heterogeneous disease for which alterations in DNA methylation patterns have been shown to be of biological and clinical importance. Here we report on the integrated analysis of molecular alterations including the methylation status of 27 gene promoters analyzed by highly quantitative pyrosequencing, and the association to gene expression, germline genotype and clinical parameters including survival. Breast cancer specific deregulation of DNA methylation (both hyper- and hypomethylation) was found in twenty genes including ACVR1, OGG1, IL8 and TFF1. The methylation level in the promoter regions was significantly negatively correlated to gene expression for twelve genes (such as MST1R, ST6GAL1 and TFF1) indicating that a gain of aberrant methylation (hypermethylation) inhibits gene expression. Multiple associations between molecular and clinical parameters were identified, and multivariate statistical analysis demonstrated that methylation was more strongly associated to clinical parameters than gene expression for the investigated genes. The methylation level of BCAP31 and OGG1 showed significant association to survival, and these associations were validated in a larger patient cohort (The Cancer Genome Atlas). Our study provides evidence for the promise of DNA methylation alterations for clinical applications.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital 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.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Hiroko K
authors.initials: HK
authors.lastname: Solvang
authors.forename: Christian
authors.initials: C
authors.lastname: Daviaud
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D005854:Germ Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D054928:Validation Studies as Topic
chemical_list: D014408:Biomarkers, Tumor
keywords: SNP; breast cancer; clinical parameters; gene expression; methylation; survival