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

被引：51

作者：

de Cubas, Aguirre A. ^{[1
]}

Korpershoek, Esther ^{[2
]}

Inglada-Perez, Lucia ^{[1
,3
]}

Letouze, Eric ^{[4
]}

Curras-Freixes, Maria ^{[1
]}

Fernandez, Agustin F. ^{[5
]}

Comino-Mendez, Inaki ^{[1
]}

Schiavi, Francesca ^{[6
]}

Mancikova, Veronika ^{[1
]}

Eisenhofer, Graeme ^{[7
,8
]}

Mannelli, Massimo ^{[9
]}

Opocher, Guiseppe ^{[6
,10
]}

Timmers, Henri ^{[11
]}

Beuschlein, Felix ^{[12
]}

de Krijger, Ronald ^{[13
]}

Cascon, Alberto ^{[1
,3
]}

Rodriguez-Antona, Cristina ^{[1
,3
]}

Fraga, Mario F. ^{[5
,14
]}

Favier, Judith ^{[15
,16
]}

Gimenez-Roqueplo, Anne-Paule ^{[15
,16
,17
,18
]}

Robledo, Mercedes ^{[1
,3
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain

[2] Erasmus MC, Univ Med Ctr, Inst Canc, Dept Pathol, Rotterdam, Netherlands

[3] Ctr Invest Biomed Red Enfermedades Rares CIBERER, Madrid, Spain

[4] Ligue Natl Contre Le Canc, Programme Cartes Identite Tumeurs, Paris, France

[5] Univ Oviedo, HUCA, Inst Oncol Asturias IUOPA, Canc Epigenet Lab, Asturias, Spain

[6] Veneto Inst Oncol, Familial Canc Clin, Padua, Italy

[7] Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany

[8] Tech Univ Dresden, Med Clin 3, D-01062 Dresden, Germany

[9] Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy

[10] Univ Padua, Dept Med, Padua, Italy

[11] Radboud Univ Nijmegen, Med Ctr, Internal Med, NL-6525 ED Nijmegen, Netherlands

[12] Univ Munich, Univ Hosp, Dept Internal Med Campus Innenstadt 4, Munich, Germany

[13] Erasmus MC, Univ Med Ctr, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands

[14] CNB CSIC, Natl Biotechnol Ctr, Dept Immunol & Oncol, Madrid, Spain

[15] Paris Cardiovasc Res Ctr PARCC, INSERM, UMR970, Paris, France

[16] Univ Paris 05, Sorbonne Paris Cite, Fac Med, Paris, France

[17] Hop Europeen Georges Pompidou, AP HP, Serv Genet, Paris, France

[18] Natl Canc Inst, Rare Adrenal Canc Network Cort Medullosurrenale T, Paris, France

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 13期

关键词：

MALIGNANT PHEOCHROMOCYTOMAS; MUTATIONS; EXPRESSION; COMPLEX; PROLIFERATION; TRANSCRIPTION; ELONGATION; INHIBITOR; RECEPTORS; PHENOTYPE;

D O I：

10.1158/1078-0432.CCR-14-2804

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 [Delta beta(metastatic-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. (C) 2015 AACR.

引用

页码：3020 / 3030

页数：11

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