TY - JOUR
T1 - DNA methylation profiling in pheochromocytoma and paraganglioma reveals diagnostic and prognostic markers
AU - De Cubas, Aguirre A.
AU - Korpershoek, Esther
AU - Inglada-Pérez, Lucia
AU - Letouzé, Eric
AU - Currás-Freixes, Maria
AU - Fernández, Agustin F.
AU - Comino-Méndez, Iñaki
AU - Schiavi, Francesca
AU - Mancikova, Veronika
AU - Eisenhofer, Graeme
AU - Mannelli, Massimo
AU - Opocher, Guiseppe
AU - Timmers, Henri
AU - Beuschlein, Felix
AU - De Krijger, Ronald
AU - Cascon, Alberto
AU - Rodríguez-Antona, Cristina
AU - Fraga, Mario F.
AU - Favier, Judith
AU - Gimenez-Roqueplo, Anne Paule
AU - Robledo, Mercedes
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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 [Dbmetastatic-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.
AB - 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 [Dbmetastatic-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.
UR - http://www.scopus.com/inward/record.url?scp=84942239095&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-2804
DO - 10.1158/1078-0432.CCR-14-2804
M3 - Article
C2 - 25825477
AN - SCOPUS:84942239095
SN - 1078-0432
VL - 21
SP - 3020
EP - 3030
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -