Phenylethanolamine N-methyltransferase downregulation is associated with malignant pheochromocytoma/paraganglioma
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Seung Eun Lee1,*, Ensel Oh3,4,*, Boram Lee2, Yu Jin Kim3, Doo-Yi Oh3,4, Kyungsoo Jung3,4, Jong-Sun Choi5, Junghan Kim6, Sung Joo Kim6, Jung Wook Yang7, Jungsuk An8, Young Lyun Oh2, Yoon-La Choi2,3,4
1Department of Pathology, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Korea
2Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
5The Center for Anti-Cancer Companion Diagnostics, School of Biological Science, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea
6Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
7Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea
8Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea
*These authors contributed equally to this work
Yoon-La Choi, e-mail: firstname.lastname@example.org
Young Lyun Oh, e-mail: email@example.com
Keywords: pheochromocytoma/paraganglioma, phenylethanolamine N-methyltransferase, biomarker, metastasis, endocrine tumors
Received: May 22, 2015 Accepted: February 10, 2016 Published: March 21, 2016
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.
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