Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, 530021, China.
Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
Sci Rep. 2017 Oct 27;7(1):14200. doi: 10.1038/s41598-017-14314-y.
Clear-cell renal cell carcinoma (ccRCC) is a common aggressive urinary malignant tumor that cannot be easily diagnosed at an early stage. The DNA methylation occurs within promoter before precancerous lesion plays a pivotal role that could help us in diagnosing and understanding ccRCC. In this study, based on a whole-genome promoter DNA methylation profiling, we used shrunken centroids classifier method to identify a CpG-based biomarker that is capable of differentiating between ccRCC tumor and adjacent tissues. The biomarker was validated in 19 ccRCCs and three public datasets. We found that both CYP4B1 and RAB25 are downregulated with promoter hypermethylation and CA9 is upregulated with promoter hypomethylation, and we validated their mRNA differential expressions in 19 ccRCCs and 10 GEO datasets. We further confirmed that hypermethylated RAB25 is inversely correlated with its mRNA level. Log-rank test showed that ccRCC patients with low levels of CA9 promoter methylation had a higher survival rate. This reveals clinically a potential biomarker for use in early detection for ccRCC, and provides a better understanding of carcinogenesis.
肾透明细胞癌（ccRCC）是一种常见的侵袭性泌尿系统恶性肿瘤，在早期阶段不易诊断。癌前病变前的 DNA 甲基化在启动子内发生，在诊断和理解 ccRCC 方面起着关键作用。在这项研究中，我们基于全基因组启动子 DNA 甲基化谱，使用收缩质心法分类器方法来识别一种基于 CpG 的生物标志物，该标志物能够区分 ccRCC 肿瘤和相邻组织。该生物标志物在 19 例 ccRCC 肿瘤和三个公共数据集进行了验证。我们发现 CYP4B1 和 RAB25 的启动子均发生高甲基化而下调，CA9 的启动子发生低甲基化而上调，我们在 19 例 ccRCC 肿瘤和 10 个 GEO 数据集中验证了它们的 mRNA 差异表达。我们进一步证实，RAB25 的高甲基化与其 mRNA 水平呈负相关。对数秩检验显示，CA9 启动子低甲基化的 ccRCC 患者的生存率更高。这揭示了临床上用于 ccRCC 早期检测的潜在生物标志物，并提供了对致癌作用的更好理解。
