Murata Asuka, Baba Yoshifumi, Watanabe Masayuki, Shigaki Hironobu, Miyake Keisuke, Ishimoto Takatsugu, Iwatsuki Masaaki, Iwagami Shiro, Yoshida Naoya, Oki Eiji, Morita Masaru, Nakao Mitsuyoshi, Baba Hideo
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto City, Kumamoto, Japan.
Ann Surg Oncol. 2014 Apr;21(4):1166-74. doi: 10.1245/s10434-013-3414-7. Epub 2013 Dec 7.
Insulin like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, to our knowledge, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC).
The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfite pyrosequencing assay with 216 ESCC tissue specimens.
Twelve (40 %) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42 %) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean 23 %) than IGF2 non-LOI cases (37 %). The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality.
The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker.
胰岛素样生长因子2基因（IGF2）通常是印记基因。人类中IGF2印记缺失（LOI）与癌症风险增加相关，且受称为差异甲基化区域（DMRs）的富含CpG的区域控制。具体而言，IGF2 DMR0处的甲基化水平与IGF2 LOI相关，是IGF2 LOI的一个潜在替代标志物。IGF2 DMR0低甲基化与结直肠癌预后不良之间的关系已得到证实。然而，据我们所知，尚无研究探讨食管鳞状细胞癌（ESCC）中IGF2 DMR0甲基化水平、LOI与临床结局之间的关系。
使用ApaI多态性筛选IGF2印记状态，并通过免疫组织化学对30例ESCC组织标本评估IGF2蛋白表达。对于生存分析，使用亚硫酸氢盐焦磷酸测序法对216例ESCC组织标本测量IGF2 DMR0甲基化。
30例中有12例（40%）信息明确（即ApaI杂合子），12例信息明确的病例中有5例（42%）表现出IGF2 LOI。IGF2 LOI病例的DMR0甲基化水平（平均23%）低于IGF2非LOI病例（37%）。IGF2 DMR0甲基化水平与IGF2蛋白表达显著相关。在202例符合生存分析条件的患者中，IGF2 DMR0低甲基化与较高的癌症特异性死亡率显著相关。
ESCC中IGF2 DMR0甲基化水平与IGF2 LOI及IGF2蛋白表达相关。此外，IGF2 DMR0低甲基化与较短的生存时间相关，提示其作为预后生物标志物的潜在作用。
