Epigenetic Dysregulation of 5-hydroxymethylcytosine in Well-Differentiated Pancreatic Neuroendocrine Tumors

• Published in: Applied immunohistochemistry & molecular morphology Vol. 30; no. 2; p. e11
• Main Authors: Sharma, Aarti E, Olivas, Andrea, Parilla, Megan, Yassan, Lindsay, Wang, Hanlin, Zhang, Sharon S, Weber, Christopher, Keutgen, Xavier M, Hart, John, Krausz, Thomas, Setia, Namrata
• Format: Journal Article
• Language: English
• Published: United States 01.02.2022
• Subjects: 5-Methylcytosine - analogs & derivatives; Epigenesis, Genetic; Female; Humans; Mitotic Index; Neuroendocrine Tumors - metabolism; Pancreatic Neoplasms - metabolism
• ISSN: 1533-4058
• DOI: 10.1097/PAI.0000000000000982

Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors.