Kinugawa Yasuhiro, Uehara Takeshi, Sano Kenji, Matsuda Kazuyuki, Maruyama Yasuhiro, Kobayashi Yukihiro, Nakajima Tomoyuki, Hamano Hideaki, Kawa Shigeyuki, Higuchi Kayoko, Hosaka Noriko, Shiozawa Satoshi, Ishigame Hiroki, Ota Hiroyoshi
From the *Department of Laboratory Medicine, and †Department of Gastroenterology, Shinshu University School of Medicine; ‡Center for Health, Safety, and Environmental Management, Shinshu University; §Department of Pathology, Aizawa Hospital, Matsumoto; ∥Department of Pathology, Nagano Municipal Hospital, Nagano; ¶Department of Pathology, Saku Central Hospital, Saku; and #Department of Biomedical Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Pancreas. 2017 May/Jun;46(5):614-618. doi: 10.1097/MPA.0000000000000804.
Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP.
Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing.
Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP.
These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.
自身免疫性胰腺炎（AIP）是一种病因不明的典型IgG4相关性炎症性疾病。为阐明AIP导致癌变的机制，我们重点研究了AIP中的甲基化异常和KRAS突变。
选择在胰腺癌中表现出高甲基化的6个肿瘤抑制基因（NPTX2、细胞周期蛋白D2、叉头框蛋白E1、组织因子途径抑制物2、前脑啡肽原和p16），对10例AIP标本、10例无AIP病史的胰腺腺癌病例（包含癌区（CAs）和非癌区（NCAs））以及11例正常胰腺（NP）样本进行定量SYBR Green甲基化特异性聚合酶链反应。还采用直接测序法研究了第12、13和61密码子处的KRAS突变。
分别在1例、2例、2例、0例、2例和0例CA病例中，NPTX2、细胞周期蛋白D2、叉头框蛋白E1、组织因子途径抑制物2、前脑啡肽原和p16中检测到高甲基化事件（≥10%），但在AIP、NCA和NP的这6个候选基因中未检测到。然而，AIP中组织因子途径抑制物2的甲基化率显著高于NCA和NP。KRAS的直接测序结果显示AIP中无单点突变。
这些是首次对AIP中的甲基化异常进行特征描述的研究。AIP的炎症状态可能与癌变有关。进一步的研究将阐明与AIP癌变相关的甲基化异常。
