O 6 -methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrin
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RESEARCH ARTICLE
Open Access
O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms Hirofumi Watanabe1, Yuto Yamazaki1, Fumiyoshi Fujishima1, Komoto Izumi2,3, Masayuki Imamura2, Susumu Hijioka4, Kazuhiro Toriyama5, Yasushi Yatabe6, Atsushi Kudo7, Fuyuhiko Motoi8, Michiaki Unno9 and Hironobu Sasano1*
Abstract Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results: In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki67 labeling index (GLUT2 score: P = 0.0045, ρ = − 0.4570; MGMT score: P = 0.0064, ρ = − 0.4399; H-score: P = 0.0110, ρ = − 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients. Keywords: Neuroendocrine neoplasm, O6-methylguanine DNA methyltransferase, Glucose transporter 2, Immunohistochemistry
* Correspondence: [email protected] 1 Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licen
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