Beeghly A C, Katsaros D, Wiley A L, Rigault de la Longrais I A, Prescott A T, Chen H, Puopolo M, Rutherford T J, Yu H
Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT, 06520-8034, USA.
J Cancer Res Clin Oncol. 2007 Oct;133(10):713-23. doi: 10.1007/s00432-007-0211-3. Epub 2007 Jun 14.
The insulin-like growth factor-II (IGF-II) gene has four promoters that produce distinct transcripts which vary by tissue type and developmental stage. Dysregulation of normal promoter usage has been shown to occur in cancer; DNA methylation regulates promoter use. Thus, we sought to examine if DNA methylation varies among IGF-II promoters in ovarian cancer and if methylation patterns are related to clinical features of the disease.
Tumor tissue, clinical data, and follow-up information were collected from 215 patients diagnosed with primary epithelial ovarian cancer. DNA extracted from tumor tissues was analyzed for IGF-II promoter methylation with seven methylation specific PCR (MSP) assays: three for promoter 2 (P2) and two assays each for promoters 3 and 4 (P3 and P4).
Methylation was found to vary among the seven assays: 19.3% in P2A, 45.6% in P2B, 50.9% in P2C, 48.4% in P3A, 13.1% in P3B, 5.1% in P4A, and 6.1% in P4B. Methylation in any of the three P2 assays was associated with high tumor grade (P = 0.043), suboptimal debulking (P = 0.036), and disease progression [hazards ratio (HR) = 1.73, 95% confidence interval (CI) 1.09-2.74]. When comparing promoter methylation patterns, differential methylation of P2 and P3 was found to be associated with disease prognosis; patients with P3 but not P2 methylation were less likely to have disease progression (HR = 0.39, 95% CI 0.17-0.91) compared to patients with P2 but not P3 methylation.
This study shows that methylation varies among three IGF-II promoters in ovarian cancer and that this variation seems to have biologic implications as it relates to clinical features and prognosis of the disease.
胰岛素样生长因子-II（IGF-II）基因有四个启动子，可产生因组织类型和发育阶段而异的不同转录本。已证明在癌症中会出现正常启动子使用的失调；DNA甲基化调节启动子的使用。因此，我们试图研究在卵巢癌中IGF-II启动子之间的DNA甲基化是否存在差异，以及甲基化模式是否与该疾病的临床特征相关。
收集了215例诊断为原发性上皮性卵巢癌患者的肿瘤组织、临床数据和随访信息。用七种甲基化特异性PCR（MSP）分析方法对从肿瘤组织中提取的DNA进行IGF-II启动子甲基化分析：三种用于启动子2（P2），两种分别用于启动子3和4（P3和P4）。
发现七种分析方法中的甲基化情况各不相同：P2A为19.3%，P2B为45.6%，P2C为50.9%，P3A为48.4%，P3B为13.1%，P4A为5.1%，P4B为6.1%。三种P2分析方法中任何一种的甲基化都与高肿瘤分级（P = 0.043）、减瘤不充分（P = 0.036）和疾病进展相关[风险比（HR）= 1.73，95%置信区间（CI）1.09 - 2.74]。比较启动子甲基化模式时，发现P2和P3的差异甲基化与疾病预后相关；与P2甲基化但P3未甲基化的患者相比，P3甲基化但P2未甲基化的患者疾病进展的可能性较小（HR = 0.39，95% CI 0.17 - 0.91）。
本研究表明，卵巢癌中三种IGF-II启动子的甲基化存在差异，并且这种差异似乎具有生物学意义，因为它与该疾病的临床特征和预后相关。
