Department of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, Germany.
Department of Urology, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany.
Int J Mol Sci. 2022 May 10;23(10):5327. doi: 10.3390/ijms23105327.
Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70−0.88, p < 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001−0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p < 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.
人类组织中 DNA 甲基化的年龄依赖性和非年龄依赖性改变与许多恶性和非恶性人类疾病的发展在功能上相关。对 TCGA-KIRC 数据进行了生物统计学分析，以鉴定可能导致正常肾脏组织肿瘤风险的具有年龄依赖性 DNA 甲基化的新基因座。通过对包括 239 份正常尸检、157 份组织病理学肿瘤旁正常和 143 对肿瘤肾脏样本在内的 539 份组织进行焦磷酸测序，评估 ANKRD34B 和 ZIC1 作为候选基因。所有候选 CpG 基因座均显示出相对甲基化水平与年龄之间的强相关性（R = 0.70-0.88，p < 2×10-16），并且 10 个基因座中有 7 个能够预测正常肾脏组织中的实际年龄，解释了 84%的方差（R = 0.92）。此外，与正常尸检组织相比，肿瘤旁组织中 10 个 CpG 基因座中有 9 个表现出明显的年龄依赖性甲基化增加（p = 0.001-0.028）。比较肿瘤和配对的肿瘤旁组织显示出两个患者簇表现出高甲基化，一个簇没有明显的甲基化变化，而较小的簇在肿瘤中表现出低甲基化（p < 1×10-10）。总之，我们的结果表明，除了年龄因素外，正常肾脏组织中还存在肾癌的其他甲基化风险因素。同时存在肿瘤特异性高甲基化表明这些基因座的一部分是表观遗传肾癌易感性的候选基因。
