Yoon Hyung-Yoon, Kim Yong-June, Kim Ji Sang, Kim Young-Won, Kang Ho Won, Kim Won Tae, Yun Seok-Joong, Ryu Keun Ho, Lee Sang-Cheol, Kim Wun-Jae
Advanced Technology Korea, Cheongju 28637, Republic of Korea.
Department of Urology, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea.
Oncol Rep. 2016 Feb;35(2):1195-203. doi: 10.3892/or.2015.4409. Epub 2015 Nov 11.
DNA methylation is a frequent and early epigenetic event with potential application as a biomarker for cancer detection and an indicator of disease evolution. The aim of the present study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation in samples from long-term follow-up patients with non-muscle invasive bladder cancer (NMIBC). Candidate methylation markers were selected from our previously published genome-wide methylation profiles. The clinical relevance of candidate methylation markers was determined by quantitative pyrosequencing analysis of 136 human bladder specimens (8 normal controls and 128 NMIBCs). The reversibility of DNA methylation was examined by 5-Aza-CdR treatment in human bladder cancer cell lines. The methylation patterns of candidate markers were significantly associated with aggressive clinicopathological features. In multivariate regression analysis, hypermethylation of radial spoke head 9 homolog (RSPH9) was an independent predictor of disease recurrence (hazard ratio, 3.02; P=0.001) and progression (hazard ratio, 8.25; P=0.028). The methylation level of RSPH9 decreased with 5-Aza-CdR treatment and progressively increased in its absence in bladder cancer cell lines. RSPH9 methylation is an independent prognostic indicator in NMIBC patients, and could be of value for the assessment of disease recurrence and progression and for clinical decision-making regarding treatment.
DNA甲基化是一种常见的早期表观遗传事件，具有作为癌症检测生物标志物和疾病进展指标的潜在应用价值。本研究的目的是通过对长期随访的非肌层浸润性膀胱癌（NMIBC）患者样本中的DNA甲基化进行微阵列分析，确定用于预测患者预后的新型甲基化标志物。候选甲基化标志物是从我们之前发表的全基因组甲基化图谱中筛选出来的。通过对136份人类膀胱标本（8份正常对照和128份NMIBC）进行定量焦磷酸测序分析，确定候选甲基化标志物的临床相关性。通过在人膀胱癌细胞系中用5-氮杂-2'-脱氧胞苷（5-Aza-CdR）处理来检测DNA甲基化的可逆性。候选标志物的甲基化模式与侵袭性临床病理特征显著相关。在多变量回归分析中，辐条头9同源物（RSPH9）的高甲基化是疾病复发（风险比，3.02；P=0.001）和进展（风险比，8.25；P=0.028）的独立预测因子。在膀胱癌细胞系中，RSPH9的甲基化水平随着5-Aza-CdR处理而降低，在未处理时逐渐升高。RSPH9甲基化是NMIBC患者的独立预后指标，对于评估疾病复发和进展以及治疗的临床决策可能具有价值。
