title: Promoter methylation of RASSF1A, RARbeta and DAPK predict poor prognosis of patients with malignant mesothelioma.
abstract: Hypermethylation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothelioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothelioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) while hypermethylation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RARbeta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RARbeta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P=0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P=0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene alone on overall survival.
authors.affiliation: Department of Medical Oncology, Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany. jr.fischer@klinik-loewenstein.de
authors.forename: Jürgen R
authors.initials: JR
authors.lastname: Fischer
authors.forename: Ute
authors.initials: U
authors.lastname: Ohnmacht
authors.forename: Norman
authors.initials: N
authors.lastname: Rieger
authors.forename: Marius
authors.initials: M
authors.lastname: Zemaitis
authors.forename: Clemens
authors.initials: C
authors.lastname: Stoffregen
authors.forename: Michael
authors.initials: M
authors.lastname: Kostrzewa
authors.forename: Erika
authors.initials: E
authors.lastname: Buchholz
authors.forename: Christian
authors.initials: C
authors.lastname: Manegold
authors.forename: Harald
authors.initials: H
authors.lastname: Lahm
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000097:blood; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases