Sakurai Naoko, Shibata Tomoyuki, Nakamura Masakatsu, Takano Hikaru, Hayashi Tasuku, Ota Masafumi, Nomura-Horita Tomoe, Hayashi Ranji, Shimasaki Takeo, Ostuka Toshimi, Tahara Tomomitsu, Arisawa Tomiyasu
Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan.
Department of Gastroenterology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
BMC Med Genet. 2020 Oct 12;21(1):201. doi: 10.1186/s12881-020-01140-9.
CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572).
One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14 and p16 was determined by MSP; MIF genotypes were identified by PCR-SSCP.
We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14 or p16. Carrying the rs755622 C allele indicated a significantly higher risk for p14 methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16 methylation (OR, 2.57; 95% CI, 1.26-5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14 and p16 when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22-6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25-6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p = 0.022).
Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.
CDKN2A 高甲基化是与致癌作用相关的主要事件之一，在溃疡性结肠炎（UC）患者的非肿瘤性结肠黏膜中也有观察到。巨噬细胞迁移抑制因子（MIF）在促进 UC 特征性的胃肠道炎症中起关键作用。本研究的目的是探讨 CDKN2A 甲基化状态与 MIF 基因多态性（rs755622 和 rs5844572）之间的关联。
159 例诊断为 UC 的患者纳入本研究。通过甲基化特异性 PCR（MSP）确定 p14 和 p16 的甲基化状态；通过聚合酶链反应-单链构象多态性（PCR-SSCP）鉴定 MIF 基因分型。
我们发现甲基化和未甲基化 p14 或 p16 的患者在平均年龄、性别、临床类型（慢性持续型或复发/缓解型）或疾病范围方面没有差异。携带 rs755622 C 等位基因表明 p14 甲基化风险显著更高（优势比（OR），2.16；95%置信区间（CI），1.08 - 4.32；p = 0.030）；同样，在调整回归分析后，携带 rs5844572 7 重复等位基因表明 p16 甲基化风险显著更高（OR，2.57；95%CI，1.26 - 5.24；p = 0.0094）。与两个基因均未甲基化的队列相比，rs755662 C 等位基因或 rs5844572 7 重复等位基因的携带者 p14 和 p16 甲基化风险均显著更高（OR，2.70；95%CI，1.22 - 6.01；p = 0.015 和 OR，2.87；95%CI，1.25 - 6.62；p = 0.013，分别）。此外，携带 rs755622 C 等位基因与临床类型为慢性持续型和全结肠炎的原发性硬化性胆管炎（CIHM）显著相关（OR，25.9；95%CI，2.55 - 262.6；p = 0.0059 和 OR，4.38；95%CI，1.12 - 17.2；p = 0.034，分别），携带 rs5844572 的 7 重复等位基因与慢性持续型显著相关（OR，14.5；95%CI，1.46 - 144.3；p = 0.022）。
综上所述，我们的研究结果表明，与炎症相关的 MIF 基因分型可能也通过 CDKN2A 高甲基化参与促进 UC 患者的致癌作用。
