DNA methylation profiling in pheochromocytoma and paraganglioma reveals diagnostic and prognostic markers Articles uri icon

authors

  • de Cubas, Aguirre A.
  • Korpershoek, Esther
  • INGLADA PEREZ, LUCIA
  • Letouzé, Eric
  • Currás Freixes, María
  • Fernández, Agustin F.
  • Comino Méndez, Iñaki
  • Schiavi, Francesca
  • Mancikova, Veronika
  • Eisenhofer, Graeme
  • Mannelli, Massimo
  • Opocher, Guiseppe
  • Timmers, Henri
  • Beuschlein, Felix
  • de Krijger, Ronald
  • Cascón, Alberto
  • Rodríguez-Antona, Cristina
  • Fraga, Mario F.
  • Favier, Judith
  • Gimenez Roqueplo, Anne-Paule
  • Robledo, Mercedes

publication date

  • July 2015

issue

  • 13

volume

  • 21

International Standard Serial Number (ISSN)

  • 1078-0432

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

abstract

  • Purpose: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. Experimental Design: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). Results: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Deltabetametastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1&-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity...