Format

Send to

Choose Destination
Clin Cancer Res. 2015 Jul 1;21(13):3020-30. doi: 10.1158/1078-0432.CCR-14-2804. Epub 2015 Mar 30.

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers.

Author information

1
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
2
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.
3
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
4
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France.
5
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, University of Oviedo, Asturias, Spain.
6
Familial Cancer Clinic, Veneto Institute of Oncology, Padova, Italy.
7
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany. Medical Clinic III, Technische Universität Dresden, Dresden, Germany.
8
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
9
Familial Cancer Clinic, Veneto Institute of Oncology, Padova, Italy. Department of Medicine, University of Padova, Padova, Italy.
10
Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.
11
Department of Internal Medicine IV Campus Innenstadt, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
12
Department of Pathology, Josephine Nefkens Institute, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
13
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, University of Oviedo, Asturias, Spain. Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid, Spain.
14
INSERM, UMR970, Paris-Cardiovascular Research Center (PARCC), Paris, France. Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
15
INSERM, UMR970, Paris-Cardiovascular Research Center (PARCC), Paris, France. Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Service de Génétique, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. Rare Adrenal Cancer Network-Cortico Médullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France.
16
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. mrobledo@cnio.es.

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 [Δβmetastatic-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.

CONCLUSIONS:

This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases.

PMID:
25825477
DOI:
10.1158/1078-0432.CCR-14-2804
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center