RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy.
RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy.
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DOI：
10.18632/oncotarget.14391
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发表时间：
2017-01-24
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影响因子：
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通讯作者：
Sorensen KD
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作者：
Strand SH;Switnicki M;Moller M;Haldrup C;Storebjerg TM;Hedegaard J;Nordentoft I;Hoyer S;Borre M;Pedersen JS;Wild PJ;Park JY;Orntoft TF;Sorensen KD
目的：由于缺乏能够区分侵袭性和惰性前列腺癌的生物标志物，导致了对临床无关紧要的疾病的大量过度治疗。在这里，通过全基因组DNA甲基组分析，我们寻求鉴定新的生物标志物，以提高前列腺癌诊断和预后的准确性。实验设计：从Illumina Infinium HumanMethylation450珠头芯片分析21例肿瘤(T)和21例非恶性（NM）前列腺标本中选择8个新的候选标记，COL4A6、CYBA、TCAF1 （FAM115A）、HLF、LINC01341 （LOC149134）、LRRC4、PROM1和RHCG。通过甲基化特异性qPCR分析进一步研究80 NM和228 T组织样本的诊断潜力。203名丹麦根治性前列腺切除术（RP）患者（队列1）通过Kaplan-Meier、单因素和多因素Cox回归分析评估预后潜力，并在来自瑞士和美国的286名RP患者（队列2）的独立队列中进行验证。结果：8个候选基因的高甲基化具有高度的癌症特异性（曲线下面积：0.79-1.00）。此外，在队列1中，2基因组RHCG-TCAF1的高甲基化可预测生化复发（BCR），独立于既定的临床病理参数Gleason评分、病理肿瘤分期和术前PSA (HR（95%置信区间（CI））： 2.09 (1.26 - 3.46)；P = 0.004)，并且在队列2中成功验证了这一点(HR (95% CI): 1.81 (1.05 - 3.12)；P = 0.032)。结论：RHCG-TCAF1甲基化为前列腺癌的既定预后参数增加了显著的独立预后价值，因此可能有助于指导未来的治疗决策。在转化为临床应用之前，需要在大型独立队列中进行进一步的研究。
Purpose: The lack of biomarkers that can distinguish aggressive from indolent prostate cancer has caused substantial overtreatment of clinically insignificant disease. Here, by genome-wide DNA methylome profiling, we sought to identify new biomarkers to improve the accuracy of prostate cancer diagnosis and prognosis. Experimental design: Eight novel candidate markers, COL4A6, CYBA, TCAF1 (FAM115A), HLF, LINC01341 (LOC149134), LRRC4, PROM1, and RHCG, were selected from Illumina Infinium HumanMethylation450 BeadChip analysis of 21 tumor (T) and 21 non-malignant (NM) prostate specimens. Diagnostic potential was further investigated by methylation-specific qPCR analysis of 80 NM vs. 228 T tissue samples. Prognostic potential was assessed by Kaplan-Meier, uni- and multivariate Cox regression analysis in 203 Danish radical prostatectomy (RP) patients (cohort 1), and validated in an independent cohort of 286 RP patients from Switzerland and the U.S. (cohort 2). Results: Hypermethylation of the 8 candidates was highly cancer-specific (area under the curves: 0.79-1.00). Furthermore, high methylation of the 2-gene panel RHCG-TCAF1 was predictive of biochemical recurrence (BCR) in cohort 1, independent of the established clinicopathological parameters Gleason score, pathological tumor stage, and pre-operative PSA (HR (95% confidence interval (CI)): 2.09 (1.26 - 3.46); P = 0.004), and this was successfully validated in cohort 2 (HR (95% CI): 1.81 (1.05 - 3.12); P = 0.032). Conclusion: Methylation of the RHCG-TCAF1 panel adds significant independent prognostic value to established prognostic parameters for prostate cancer and thus may help to guide treatment decisions in the future. Further investigation in large independent cohorts is necessary before translation into clinical utility.