title: Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation.
abstract: Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. This study was undertaken to explore CpG methylation abnormalities in an extended tumor panel and assess possible relationships between metastatic disease and mutation status. CpG methylation was quantified by bisulfite pyrosequencing for selected TSG promoters and LINE1 repeats. Methylation indices above normal reference were observed for DCR2 (TNFRSF10D), CDH1, P16 (CDKN2A), RARB, and RASSF1A. Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome. Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease. Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue. In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival. The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series. Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. nimrod.kiss@ki.se
authors.forename: Nimrod B
authors.initials: NB
authors.lastname: Kiss
authors.forename: Andreas
authors.initials: A
authors.lastname: Muth
authors.forename: Adam
authors.initials: A
authors.lastname: Andreasson
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Janos
authors.initials: J
authors.lastname: Geli
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.forename: Bo
authors.initials: B
authors.lastname: Wängberg
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlman
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
mesh_terms: D000008:Abdominal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase