Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

• Published in: Modern pathology Vol. 20; no. 7; pp. 802 - 810
• Main Authors: Choi, In-Seon, Estecio, Marcos R H, Nagano, Yasuhiko, Kim, Do Ha, White, Jill A, Yao, James C, Issa, Jean-Pierre J, Rashid, Asif
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01-07-2007
• Subjects: Alu Elements - genetics; Cancer; Carcinoid Tumor - genetics; Carcinoid Tumor - pathology; Cell Line, Tumor; Chromosome Deletion; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 16 - genetics; Chromosomes, Human, Pair 18 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DNA Methylation; Epigenetics; Female; Genomes; Humans; Long Interspersed Nucleotide Elements - genetics; Lymphatic Metastasis; Lymphatic system; Male; Metastasis; Middle Aged; Neuroendocrine tumors; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; O-Methylguanine-DNA Methyltransferase - genetics; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pathology; Sequence Analysis, DNA - methods; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Proteins - genetics; United States > US
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.3800825

Neuroendocrine tumors including carcinoid tumors and pancreatic endocrine tumors are uncommon, and the genetic alterations in these indolent tumors are not well characterized. We studied global hypomethylation by analyzing long interspersed nucleotide elements (LINE)-1 and Alu methylation using pyrosequencing in 35 neuroendocrine tumors and corresponding normal tissue. The tumor samples were less methylated than normal tissue at LINE-1 (P=0.04) and Alu (P=0.001). The mean relative tumor hypomethylation (difference in methylation between normal tissue and in tumor) was 11.5+/-10.0 for LINE-1 and 5.8+/-6.4 for Alu, and were correlated with each other (correlation coefficient 0.6, P=0.001). Relative tumor hypomethylation of LINE-1 was higher in ileal carcinoid tumors than in non-ileal carcinoid tumors and pancreatic endocrine tumors (P=0.047), and tumors with lymph node metastasis (P=0.02), chromosome 18 loss (P=0.001) and RAS-association domain family 1, isoform A gene methylation (P=0.02). Alu methylation in tumors was inversely correlated with methylation of O(6)-methyl-guanine methyltransferase gene (P=0.02). Our study shows that hypomethylation is more common in carcinoid tumors than in pancreatic endocrine tumors and is associated with clinicopathologic features, and genetic and epigenetic alterations in these tumors, including lymph node metastasis.