Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas: Association to malignant behavior

Janos Geli, Nimrod Kiss, Mohsen Karimi, Jia Jing Lee, Martin Bäckdahl, Tomas J. Ekström, Catharina Larsson

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Purpose: This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes. Experimental Design: A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16INK4A CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14ARF, and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis. Results: Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02). Conclusion: We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.

Original languageEnglish (US)
Pages (from-to)2551-2559
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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