DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
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DOI：
10.1158/1078-0432.ccr-14-2804
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发表时间：
2015-07-01
影响因子：
11.5
通讯作者：
Robledo, Mercedes
中科院分区：
文献类型：
--
作者：
de Cubas, Aguirre A.;Korpershoek, Esther;Robledo, Mercedes
目的：嗜铬细胞瘤和副神经节瘤（PPGL）是罕见的神经内分泌肿瘤，与高度可变的术后演变。可靠的PPGL预后标志物的缺乏继续使患者管理复杂化。在这项研究中，我们探讨了全基因组DNA甲基化模式的背景下，PPGL恶性肿瘤，以确定新的预后markers.Experimental设计：我们回顾性研究了DNA甲基化模式，PPGL与无转移使用高通量DNA甲基化谱数据（Illumina 27 K），来自两个大的、充分表征的发现（n = 123; 24转移性）和初步验证（n = 154; 24转移性）系列。在第二组独立的33个石蜡包埋的PPGL（19个转移性）中通过亚硫酸氢盐焦磷酸测序进行候选CpG的额外验证：在最初的86个候选CpG中，我们成功地复制了52个（47个基因），与转移性PPGL相关。其中，48个CpG即使在校正SDHB基因型后也显示出与进展时间的显著相关性，表明它们作为独立于遗传背景的预后标志物的价值。RDBP超甲基化通过亚硫酸氢盐焦磷酸测序[Δ β]进一步验证转移性肿瘤中的负延伸因子复合物成员E（转移性-良性）= 0.29，P = 0.003; HR，1.4; 95%置信区间（CI），1.1- 2.0; P = 0.018]，并可能改变转录网络，（RERG、GPX 3和PDZK 1）凋亡、侵袭和DNA完整性的维持。这是转移性PPGL中DNA甲基化的第一个大规模研究，该研究确定并验证了预后标志物，可用于根据发生转移的风险对患者进行分层。在选择用于进一步验证的三个CpG中，一个（RDBP）被明确证实，并且可以用于根据发生转移的风险对患者进行分层。(C)2015年AACR。
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.