Purpose

Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer.

Methods

We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations.

Results

We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39).

Conclusions

Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.

中文翻译：

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美洲印第安人的血液 DNA 甲基化与肝癌：来自强心脏研究的证据

目的

过去 20 年来，美洲印第安人/阿拉斯加原住民的肝癌发病率有所上升。外周血 DNA 甲基化可能与肝癌相关，可作为癌症风险的生物标志物。我们评估了血液 DNA 甲基化与肝癌风险的关联。

方法

我们对来自亚利桑那州、俄克拉荷马州、北达科他州和南达科他州的 2324 名年龄在 45 岁至 75 岁之间的美国印第安人进行了一项前瞻性队列研究，他们在 1989 年至 1991 年间参加了强心脏研究。 确定了肝癌死亡人数 ( n = 21)使用截至 2017 年获得的死亡证明。非病例的平均随访时间 (SD) 为 25.1 (5.6) 年，病例的平均随访时间 (SD) 为 11.0 (8.8) 年。使用 MmethylationEPIC BeadChip 850 K 阵列对基线时收集的血液样本进行 DNA 甲基化评估。我们使用针对年龄、性别、中心、体重指数、低密度脂蛋白胆固醇、吸烟、饮酒和免疫细胞比例进行调整的 Cox 回归模型来检查相关性。

结果

我们确定了 9 个与肝癌相关的 CpG 位点。注释为MRFAP1的 cg16057201 ）在病例与非病例中高度甲基化（甲基化一个标准差增加的风险比 (HR) 为 1.25 (95% CI 1.14, 1.37)。其他 8 个 CpG 低甲基化，相应的 HR (95 % CI）范围从 cg04967787（注释为PPRC1 ）的 0.58（0.44，0.75）到 cg08550308 的 0.77（0.67，0.88）。我们还在之前的研究中评估了与肝癌相关的 7 个差异甲基化 CpG 位点。cg15079934 的调整后 HR（注释为LPS1 ) 为 1.93 (95% CI 1.10, 3.39)。

结论

血液 DNA 甲基化可能与肝癌死亡率相关，并且可能在肝癌的发展过程中发生改变。