Site- and Grade-specific Diversity of LINE1 Methylation Pattern in Gastroenteropancreatic Neuroendocrine Tumours

Background: Recent data indicate that gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have a hypomethylated long interspersed element (LINE1) promoter. To answer the question, of whether LINE1 may be of value in assessing the malignant potential of GEP-NETs, we analysed LINE1 methylation in different organs. Materials and Methods: A total of 58 GEP-NETs of gastric (n=14), pancreatic (n=15), small intestine (n=17), appendix (n=8), colorectal (n=4) and non-neoplastic tissues were analysed using DNA isolation, bisulphite-treatment and pyrosequencing. Results: LINE1 hypomethylation was detected in 50% of gastric, 100% pancreatic, 82% small intestine, 87.5% appendix and 100% colorectal NETs. G1 (p<0.001) and G2 (p<0.05) colorectal, and G1 (p<0.001) and G2 (p<0.001) pancreatic NETs exhibited significant LINE1 hypomethylation compared with non-neoplastic tissues. Higher rates of LINE1 hypomethylation in G2 pancreatic NETs than in G1 NETs (p<0.05) were observed. NETs exhibited a significantly lower frequency of hypomethylation in cases with lymph node metastases (p<0.05). Conclusion: LINE1 hypomethylation may serve as a marker of tumour grade and lymph node metastasis. Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous and rare tumours of epithelial origin occurring in the gastrointestinal (GI) tract exhibiting neuroendocrine differentiation (1-3). Numerous classification systems were used before the World Health Organization (WHO) classifications in 2000, subsequently revised in 2004