Data from Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior

• DOI: 10.1158/1078-0432.c.6517147.v1
• Publication Date: 2023-04-01T08:20:10Z
• Authors: Janos Geli; Nimrod Kiss; Mohsen Karimi; Jia-Jing Lee; Martin Bäckdahl; Tomas J. Ekström; Catharina Larsson

<div>Abstract<p><b>Purpose:</b> This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes.</p><p><b>Experimental Design:</b> A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, <i>p16^INK4A, CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14^ARF,</i> and <i>PTEN</i>, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean <i>Z</i> scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for <i>LINE-1</i> promoter sequences and by using luminescent methylation analysis.</p><p><b>Results:</b> Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (<i>P</i> = 0.005) and younger age at presentation (<i>P</i> < 0.007) but did not result from <i>BRAF</i> V600E mutation. Global hypomethylation of <i>LINE-1</i> elements was observed in tumors compared with normal adrenal samples (<i>P</i> < 0.02).</p><p><b>Conclusion:</b> We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.</p></div>