Yin Yifei, Lei Shuifang, Li Lixi, Yang Xiaoqin, Yin Qiming, Xu Tian, Zhou Wenjie, Li Hong, Gu Wanjian, Ma Fei, Yang Rongxi, Zhang Zhengdong
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Thyroid and Breast Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, China.
Genes Genomics. 2022 Apr;44(4):435-443. doi: 10.1007/s13258-021-01182-0. Epub 2021 Nov 12.
Altered regulatory-associated protein of mTOR, complex 1 (RPTOR) methylation levels in peripheral blood was originally discovered as breast cancer (BC)-associated risk factor in Caucasians.
To explore the relationship between RPTOR methylation and BC in the Chinese population, we conducted two independent case-control studies.
Peripheral blood samples were collected from a total of 333 sporadic BC cases and 378 healthy female controls for the DNA extraction and bisulfite-specific PCR amplification. Mass spectrometry was applied to quantitatively measure the levels of methylation. The logistic regression, Spearman's rank correlation, and Non-parametric tests were used for the statistical analyses.
In our study, we found an association between BC and RPTOR_CpG_4 hypomethylation in the general population (per-10% of methylation, OR 1.29, P = 0.012), and a weak association between BC and RPTOR_CpG_8 hypomethylation in the women with older age (per-10% of methylation, OR 2.34, P = 0.006). We also identified age as a confounder for the change of RPTOR methylation patterns, especially at RPTOR_CpG_4, which represented differential methylation comparing age groups especially in the BC cases (age < 50 years vs age ≥ 50 years by Mann-Whitney U test, P < 0.0001 for BC cases and P = 0.079 for controls).
Our study validated the association between hypomethylation of RPTOR and BC risk in the Chinese population also with weak effect and mostly for postmenopausal women. In addition, our findings provided novel insight for the regulation of DNA methylation upon aging or the change of hormone levels.
外周血中雷帕霉素靶蛋白复合物1（RPTOR）甲基化水平的改变最初被发现是高加索人群中与乳腺癌（BC）相关的风险因素。
为了探究中国人群中RPTOR甲基化与乳腺癌之间的关系，我们开展了两项独立的病例对照研究。
共采集333例散发性乳腺癌病例和378例健康女性对照的外周血样本用于DNA提取和亚硫酸氢盐特异性PCR扩增。采用质谱法定量测定甲基化水平。采用逻辑回归、Spearman秩相关分析和非参数检验进行统计分析。
在我们的研究中，我们发现普通人群中乳腺癌与RPTOR_CpG_4低甲基化之间存在关联（甲基化每降低10%，比值比为1.29，P = 0.012），在年龄较大的女性中乳腺癌与RPTOR_CpG_8低甲基化之间存在弱关联（甲基化每降低10%，比值比为2.34，P = 0.006）。我们还确定年龄是RPTOR甲基化模式变化的混杂因素，尤其是在RPTOR_CpG_4处，这代表了不同年龄组之间的差异甲基化，特别是在乳腺癌病例中（通过Mann-Whitney U检验比较年龄<50岁与年龄≥50岁，乳腺癌病例P<0.0001，对照组P = 0.079）。
我们的研究验证了中国人群中RPTOR低甲基化与乳腺癌风险之间的关联，且作用较弱，主要见于绝经后女性。此外，我们的研究结果为衰老或激素水平变化时DNA甲基化的调控提供了新的见解。
