Cancer Research Program, PSMAR-IMIM (Hospital del Mar Medical Research Institute), Carrer Dr. Aiguader 88, 08003 Barcelona, Spain.
Universitat Pompeu Fabra, Plaça de la Mercè 10, 08002 Barcelona, Spain.
Cancer Treat Rev. 2017 Dec;61:82-93. doi: 10.1016/j.ctrv.2017.10.004. Epub 2017 Nov 6.
Despite adequate treatment and follow-up, around one fifth of patients with localized bladder cancer will present with disease progression. Adequate prognostic biomarkers are lacking to define patients who are at risk. Mutations in chromatin remodeling genes are more frequently found in bladder cancer than in any other solid tumor. However, the prognostic relevance of epigenetic dysregulation has not been established and may offer an opportunity for biomarker discovery.
Looking for prognostic epigenetic factors, we performed a comprehensive PubMed search using keywords such as "bladder cancer", "chromatin remodeling", "gene methylation" and "epigenetics". We only included studies reporting on the association of epigenetic markers with prognostic outcomes such as recurrence, progression or survival.
Of 1113 results, 87 studies met the inclusion criteria, which represented a total of 85 epigenetic markers with potential prognostic relevance. No prospective studies were identified. Seventy-three percent (64/87) of the studies involved mixed cohorts of muscle invasive and non-muscle invasive bladder cancer. Promoter methylation of genes with putative prognostic value affected cellular processes such as cell cycle, apoptosis, cell-adhesion or migration, as well as critical pathways such as MAP-kinase or Wnt. Alteration of chromatin regulatory elements suggest a prognostic relevance alterations leading to a predominantly silenced chromatin state.
The prognostic impact of epigenetic alterations in bladder cancer is still unclear. Prospective evaluation of methylation marks and chromatin remodeling gene alterations using consistent methods and criteria is warranted.
尽管进行了充分的治疗和随访，仍有五分之一的局限性膀胱癌患者会出现疾病进展。目前缺乏充分的预后生物标志物来确定处于危险中的患者。染色质重塑基因的突变在膀胱癌中的发生率高于任何其他实体瘤。然而，表观遗传失调的预后相关性尚未确定，这可能为生物标志物的发现提供机会。
为了寻找具有预后意义的表观遗传因素，我们使用了“膀胱癌”、“染色质重塑”、“基因甲基化”和“表观遗传学”等关键词，在 PubMed 上进行了全面搜索。我们只纳入了报道表观遗传标记物与复发、进展或生存等预后结果相关的研究。
在 1113 项结果中，有 87 项研究符合纳入标准，共涉及 85 个具有潜在预后意义的表观遗传标记物。没有前瞻性研究。73%（64/87）的研究涉及肌层浸润性和非肌层浸润性膀胱癌的混合队列。具有潜在预后价值的基因启动子甲基化影响细胞周期、凋亡、细胞黏附和迁移等细胞过程，以及 MAP 激酶或 Wnt 等关键途径。染色质调节元件的改变表明预后相关的改变导致了主要沉默的染色质状态。
表观遗传改变对膀胱癌的预后影响尚不清楚。需要使用一致的方法和标准，对甲基化标记和染色质重塑基因改变进行前瞻性评估。
