Lee Seung Eun, Oh Ensel, Lee Boram, Kim Yu Jin, Oh Doo-Yi, Jung Kyungsoo, Choi Jong-Sun, Kim Junghan, Kim Sung Joo, Yang Jung Wook, An Jungsuk, Oh Young Lyun, Choi Yoon La
Department of Pathology, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Korea.
Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Oncotarget. 2016 Apr 26;7(17):24141-53. doi: 10.18632/oncotarget.8234.
Malignant pheochromocytoma/paraganglioma (PCC/PGL) is defined by the presence of metastases at non-chromaffin sites, which makes it difficult to prospectively diagnose malignancy. Here, we performed array CGH (aCGH) and paired gene expression profiling of fresh, frozen PCC/PGL samples (n = 12), including three malignant tumors, to identify genes that distinguish benign from malignant tumors. Most PCC/PGL cases showed few copy number aberrations, regardless of malignancy status, but mRNA analysis revealed that 390 genes were differentially expressed in benign and malignant tumors. Expression of the enzyme, phenylethanolamine N-methyltransferase (PNMT), which catalyzes the methylation of norepinephrine to epinephrine, was significantly lower in malignant PCC/PGL as compared to benign samples. In 62 additional samples, we confirmed that PNMT mRNA and protein levels were decreased in malignant PCC/PGL using quantitative real-time polymerase chain reaction and immunohistochemistry. The present study demonstrates that PNMT downregulation correlates with malignancy in PCC/PGL and identifies PNMT as one of the most differentially expressed genes between malignant and benign tumors.
恶性嗜铬细胞瘤/副神经节瘤（PCC/PGL）的定义是在非嗜铬部位出现转移，这使得前瞻性诊断恶性肿瘤变得困难。在此，我们对新鲜冷冻的PCC/PGL样本（n = 12）进行了阵列比较基因组杂交（aCGH）和配对基因表达谱分析，其中包括三个恶性肿瘤，以确定区分良性和恶性肿瘤的基因。大多数PCC/PGL病例，无论恶性状态如何，显示出很少的拷贝数畸变，但mRNA分析显示，390个基因在良性和恶性肿瘤中差异表达。催化去甲肾上腺素甲基化生成肾上腺素的苯乙醇胺N-甲基转移酶（PNMT）的表达，在恶性PCC/PGL中比良性样本显著降低。在另外62个样本中，我们使用定量实时聚合酶链反应和免疫组织化学证实，恶性PCC/PGL中PNMT mRNA和蛋白水平降低。本研究表明，PNMT下调与PCC/PGL的恶性程度相关，并确定PNMT是恶性和良性肿瘤之间差异表达最明显的基因之一。
