Geybels Milan S, Fang Min, Wright Jonathan L, Qu Xiaoyu, Bibikova Marina, Klotzle Brandy, Fan Jian-Bing, Feng Ziding, Ostrander Elaine A, Nelson Peter S, Stanford Janet L
Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, USA.
Oncotarget. 2017 Sep 15;8(48):84338-84348. doi: 10.18632/oncotarget.20940. eCollection 2017 Oct 13.
Prostate cancer (PCa) with loss of the tumor suppressor gene has an unfavorable prognosis. DNA methylation profiles associated with loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors.
The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles. Patients were followed for PCa recurrence on average for 8 years after diagnosis.
The study included 471 patients with data on loss, and the frequency of hemi- and homozygous loss was 10.0% and 4.5%, respectively. Loss of was associated with a significantly higher risk of recurrence (any vs. no loss; HR = 1.74; 95% CI: 1.03-2.93). Hazard ratios for hemi- and homozygous loss were 1.39 (95% CI: 0.73-2.64) and 2.84 (95% CI: 1.30-6.19), respectively. Epigenome-wide methylation profiling identified 4,208 differentially methylated CpGs (FDR Q-value < 0.01) in tumors with any versus no loss. There were no genome-wide significant differentially methylated CpGs in homo- versus hemizygous deleted tumors. Tumor methylation data were used to build a methylation signature of loss in our cohort, which was confirmed in TCGA, and included CpGs in , , , , and .
Loss of was positively associated with PCa recurrence. Prostate tumors with loss harbor a distinct methylation signature, and these aberrantly methylated CpG sites may mediate tumor progression when is deleted.
肿瘤抑制基因缺失的前列腺癌（PCa）预后不良。与该基因缺失相关的DNA甲基化图谱可能为这些侵袭性更强、临床相关肿瘤的潜在机制提供进一步的见解。
该队列包括临床局限性PCa患者。取自原发性肿瘤的样本用于通过荧光原位杂交（FISH）确定基因组缺失，并分析全表观基因组DNA甲基化图谱。患者在诊断后平均随访8年以观察PCa复发情况。
该研究纳入了471例有该基因缺失数据的患者，半合子和纯合子缺失的频率分别为10.0%和4.5%。该基因缺失与显著更高的复发风险相关（有缺失与无缺失相比；风险比[HR]=1.74；95%置信区间[CI]：1.03 - 2.93）。半合子和纯合子缺失的风险比分别为1.39（95%CI：0.73 - 2.64）和2.84（95%CI：1.30 - 6.19）。全表观基因组甲基化分析在有任何该基因缺失与无缺失的肿瘤中鉴定出4208个差异甲基化的CpG位点（错误发现率[FDR]Q值<0.01）。在纯合子与半合子缺失的肿瘤中，未发现全基因组范围内显著的差异甲基化CpG位点。肿瘤甲基化数据用于构建我们队列中该基因缺失的甲基化特征，该特征在癌症基因组图谱（TCGA）中得到证实，并且包括该基因、、、和中的CpG位点。
该基因缺失与PCa复发呈正相关。有该基因缺失的前列腺肿瘤具有独特的甲基化特征，并且当该基因缺失时，这些异常甲基化的CpG位点可能介导肿瘤进展。
