Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.
Department of Surgery, Kansai Electric Power Hospital, Osaka, 553-0003, Japan.
BMC Cancer. 2020 Dec 7;20(1):1195. doi: 10.1186/s12885-020-07579-6.
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.
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).
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 Ki-67 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.
The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.
链脲佐菌素（STZ）用于治疗胰腺（PanNET）和胃肠道（GI-NET）神经内分泌肿瘤，但在 GI-NET 中的治疗效果相对较低。因此，选择可能受益于 STZ 治疗的 GI-NET 患者至关重要。STZ 通过葡萄糖转运蛋白 2（GLUT2）进入细胞，O6-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）的缺失也增加了其治疗效果。因此，GLUT2 高和 MGMT 低状态可以作为 STZ 的替代标志物。
在这项研究中，我们研究了胃肠道神经内分泌肿瘤（NEN）中的 MGMT 和 GLUT2 状态。我们研究了 84 例 NEN 病例：33 例前肠和 37 例后肠 GI-NETs 和 14 例胃肠道神经内分泌癌（GI-NECs）。
在 GI-NETs 中，MGMT 评分≥2 和≥3 分别为 77%（54/70）和 56%（39/70），GLUT2 评分≥4 和≥6 分别为 30%（21/70）和 4.3%（3/70）。甲基化特异性聚合酶链反应显示，仅在 2/14 例 GI-NEC 中检测到 MGMT 启动子甲基化，而在纳入的 GI-NETs 中均未检测到。GLUT2（GLUT2 评分）和 MGMT 免疫反应性（MGMT 和 H 评分）与 Ki-67 标记指数均呈显著相关性（GLUT2 评分：P=0.0045，ρ=-0.4570；MGMT 评分：P=0.0064，ρ=-0.4399；H 评分：P=0.0110，ρ=-0.4135），MGMT 免疫反应性与 GLUT2 免疫反应性呈显著相关性（MGMT 评分：P=0.0198；H 评分，P=0.0004，ρ=0.5483）在后肠 NETs 中，但在前肠 NETs 中则没有。然而，在几个 GI-NET 病例中，GLUT2 和 MGMT 免疫反应性之间的上述相关性存在差异，这些病例可能是 STZ 治疗的潜在候选者。
评估 MGMT 和 GLUT2 状态可为 GI-NET 患者接受 STZ 治疗提供重要信息。
