Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Melchor Fernandez Almagro 3, Madrid E-28029, Spain.
J Transl Med. 2013 Aug 1;11:182. doi: 10.1186/1479-5876-11-182.
Array-CGH represents a comprehensive tool to discover genomic disease alterations that could potentially be applied to body fluids. In this report, we aimed at applying array-CGH to urinary samples to characterize bladder cancer.
Urinary DNA from bladder cancer patients and controls were hybridized on 44K oligonucleotide arrays. Validation analyses of identified regions and candidates included fluorescent in situ hybridization (FISH) and immunohistochemistry in an independent set of bladder tumors spotted on custom-made tissue arrays (n = 181).
Quality control of array-CGH provided high reproducibility in dilution experiments and when comparing reference pools. The most frequent genomic alterations (minimal recurrent regions) among bladder cancer urinary specimens included gains at 1q and 5p, and losses at 10p and 11p. Supervised hierarchical clustering identified the gain at 1q23.3-q24.1 significantly correlated to stage (p = 0.011), and grade (p = 0.002). The amplification and overexpression of Prefoldin (PFND2), a selected candidate mapping to 1q23.3-q24.1, correlated to increasing stage and tumor grade by means of custom-designed and optimized FISH (p = 0.013 and p = 0.023, respectively), and immunohistochemistry (p ≤0.0005 and p = 0.011, respectively), in an independent set of bladder tumors included in tissue arrays. Moreover, PFND2 overexpression was significantly associated with poor disease-specific survival (p ≤0.0005). PFND2 was amplified and overexpressed in bladder tumors belonging to patients providing urinary specimens where 1q23.3q24.1 amplification was detected by array-CGH.
Genomic profiles of urinary DNA mirrowed bladder tumors. Molecular profiling of urinary DNA using array-CGH contributed to further characterize genomic alterations involved in bladder cancer progression. PFND2 was identified as a tumor stratification and clinical outcome prognostic biomarker for bladder cancer patients.
阵列 CGH 是一种发现潜在可应用于体液的基因组疾病改变的综合工具。本研究旨在应用于尿液样本以鉴定膀胱癌。
膀胱癌患者和对照者的尿液 DNA 与 44K 寡核苷酸阵列杂交。对鉴定出的区域和候选区域的验证分析包括在定制组织阵列上的膀胱癌独立肿瘤点上进行荧光原位杂交 (FISH) 和免疫组织化学分析（n=181）。
阵列 CGH 的质量控制在稀释实验和参考池比较中提供了高度的可重复性。膀胱癌尿标本中最常见的基因组改变（最小复发区域）包括 1q 和 5p 的增益以及 10p 和 11p 的缺失。监督分层聚类鉴定出 1q23.3-q24.1 的增益与分期显著相关（p=0.011），与分级显著相关（p=0.002）。选择位于 1q23.3-q24.1 的 Prefoldin（PFND2）的扩增和过表达与 FISH（p=0.013 和 p=0.023）以及免疫组织化学（p≤0.0005 和 p=0.011）检测到的进展期和肿瘤分级呈正相关，分别为，在包含在组织阵列中的膀胱癌的独立样本中。此外，PFND2 过表达与不良疾病特异性生存显著相关（p≤0.0005）。PFND2 在 array-CGH 检测到 1q23.3q24.1 扩增的患者提供的尿液标本中的膀胱癌中扩增和过表达。
尿 DNA 的基因组图谱与膀胱癌相吻合。使用阵列 CGH 对尿 DNA 进行分子谱分析有助于进一步鉴定膀胱癌进展过程中涉及的基因组改变。PFND2 被鉴定为膀胱癌患者的肿瘤分层和临床预后的生物标志物。
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