Wang Xiaoyu, Jordahl Kristina M, Zhu Chenghao, Livingstone Julie, Rhie Suhn K, Wright Jonathan L, Grady William M, Boutros Paul C, Stanford Janet L, Dai James Y
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
Cancer Epidemiol Biomarkers Prev. 2022 Jul 1;31(7):1473-1482. doi: 10.1158/1055-9965.EPI-22-0007.
Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles.
We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations.
Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant.
A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis.
This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.
前列腺癌患者在根治性前列腺切除术后预后存在异质性。包括癌症基因组图谱（TCGA）在内的基因组研究已报道了前列腺癌的分子特征，但很少有研究评估DNA甲基化谱的预后作用。
我们使用来自三个患者群体的甲基化组数据，对原发性前列腺肿瘤进行了迄今为止最大规模的甲基化组亚型分析：TCGA、在弗雷德·哈钦森癌症研究中心（FH；华盛顿州西雅图）进行的一项前列腺癌队列研究，以及加拿大国际癌症基因组联盟（ICGC）队列。在TCGA数据集中检测到四种亚型，然后将其独立应用于FH和ICGC队列数据。在上述三个患者群体中评估所确定的甲基化亚型与癌症预后的关联。
利用一组高甲基化的CpG位点，在TCGA中鉴定出四种甲基化亚型。与1型亚型相比，4型亚型在TCGA患者中生化复发（BCR）的风险比为2.09（P = 0.029）。在FH队列中，复发的风险比为2.76（P = 0.002），转移致死（转移或前列腺癌特异性死亡）结局的风险比为9.73（P = 0.002）。在加拿大ICGC队列中也观察到类似的关联模式，尽管风险比无统计学意义。
在三项有前列腺肿瘤甲基化组数据的研究中，一种高甲基化亚型与复发和死亡风险增加相关。需要进一步开展分子研究以了解甲基化亚型对癌症预后的影响。
本研究鉴定出一种DNA甲基化亚型，其与根治性前列腺切除术后前列腺癌预后较差相关。
