title: Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma.
abstract: Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, Cotswold Rd, Sutton, Surrey, United Kingdom.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kaiser
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.forename: Annamaria
authors.initials: A
authors.lastname: Brioli
authors.forename: Fabio
authors.initials: F
authors.lastname: Mirabella
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002869:Chromosome Aberrations; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality; D015676:Osteonectin; D010641:Phenotype; D011379:Prognosis; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D015676:Osteonectin; C577241:SPARC protein, human; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine