优先的 MGMT 甲基化可能使包括 SDH 缺陷型在内的一部分 KIT/PDGFRA-WT GIST 对烷化剂敏感。
Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents.
机构信息
Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.
UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
出版信息
Clin Epigenetics. 2019 Jan 7;11(1):2. doi: 10.1186/s13148-018-0594-9.
BACKGROUND
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O-methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors.
RESULTS
Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002).
CONCLUSIONS
A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.
背景
琥珀酸脱氢酶（SDH）缺陷型胃肠道间质瘤（GIST）构成了一个小型 KIT/PDGFRA-WT GIST 亚组，其特征为 DNA 甲基化，尽管广泛存在，但并非随机分布。尽管这些肿瘤通常表现惰性，但在侵袭性病例中大多对化疗药物具有耐药性。启动子甲基化诱导的 O-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）失活可提高烷化剂在神经胶质瘤、结直肠癌和弥漫性大 B 细胞淋巴瘤中的疗效。已经在一些 GIST 中发现了 MGMT 甲基化，但并未确定 SDH 状态。过去的肉瘤试验中纳入了 36 例 GIST 患者，以检测烷化剂的疗效，但结果均为阴性。然而，由于未对 GIST 进行基因型选择或进行 SDH 检测，因此可能对 MGMT 甲基化 GIST 的疗效检测存在漏诊。仅在两个病例中研究了 MGMT，结果显示基线活性。这些试验是在 Choi 标准（检测 GIST 对治疗反应的最敏感标准）之前进行的。在这种情况下，我们通过甲基化特异性 PCR 分析了 48 例具有不同病理特征的 GIST，以检测 SDH 免疫组化鉴定的 SDH 缺陷型病例中是否存在 MGMT 甲基化，从而为这些肿瘤可能使用烷化剂药物提供依据。
结果
我们的研究中 9 例 GIST 存在 SDH 缺陷，结果发现这 9 例中 MGMT 甲基化的比例明显更高（6/9-67%，而 SDH 功能正常的 GIST 中为 6/39-15%；p=0.004）。具有不同病理特征的 KIT/PDGFRA-WT GIST 也明显存在 MGMT 甲基化（11/24-46%，而 KIT/PDGFRA 突变型病例中为 1/24-4%；p=0.002）。
结论
包括最大的病理特征亚组（即 SDH 缺陷型）在内的 KIT/PDGFRA-WT GIST 的一个亚组中存在 MGMT 甲基化。这一发现可能会重新评估烷化剂治疗这些总体化疗耐药肿瘤中恶性病例的效果。
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