Cifola Ingrid, Spinelli Roberta, Beltrame Luca, Peano Clelia, Fasoli Ester, Ferrero Stefano, Bosari Silvano, Signorini Stefano, Rocco Francesco, Perego Roberto, Proserpio Vanessa, Raimondo Francesca, Mocarelli Paolo, Battaglia Cristina
Dept. of Biomedical Sciences and Technologies and CISI, University of Milan, Milan, Italy.
Mol Cancer. 2008 Jan 14;7:6. doi: 10.1186/1476-4598-7-6.
Clear cell renal carcinoma (RCC) is the most common and invasive adult renal cancer. For the purpose of identifying RCC biomarkers, we investigated chromosomal regions and individual genes modulated in RCC pathology. We applied the dual strategy of assessing and integrating genomic and transcriptomic data, today considered the most effective approach for understanding genetic mechanisms of cancer and the most sensitive for identifying cancer-related genes.
We performed the first integrated analysis of DNA and RNA profiles of RCC samples using Affymetrix technology. Using 100K SNP mapping arrays, we assembled a genome-wide map of DNA copy number alterations and LOH areas. We thus confirmed the typical genetic signature of RCC but also identified other amplified regions (e.g. on chr. 4, 11, 12), deleted regions (chr. 1, 9, 22) and LOH areas (chr. 1, 2, 9, 13). Simultaneously, using HG-U133 Plus 2.0 arrays, we identified differentially expressed genes (DEGs) in tumor vs. normal samples. Combining genomic and transcriptomic data, we identified 71 DEGs in aberrant chromosomal regions and observed, in amplified regions, a predominance of up-regulated genes (27 of 37 DEGs) and a trend to clustering. Functional annotation of these genes revealed some already implicated in RCC pathology and other cancers, as well as others that may be novel tumor biomarkers.
By combining genomic and transcriptomic profiles from a collection of RCC samples, we identified specific genomic regions with concordant alterations in DNA and RNA profiles and focused on regions with increased DNA copy number. Since the transcriptional modulation of up-regulated genes in amplified regions may be attributed to the genomic alterations characteristic of RCC, these genes may encode novel RCC biomarkers actively involved in tumor initiation and progression and useful in clinical applications.
透明细胞肾细胞癌（RCC）是最常见且侵袭性最强的成人肾癌。为了鉴定RCC生物标志物，我们研究了在RCC病理过程中受到调控的染色体区域和单个基因。我们采用了评估和整合基因组及转录组数据的双重策略，如今该策略被认为是理解癌症遗传机制最有效的方法，也是鉴定癌症相关基因最敏感的方法。
我们使用Affymetrix技术对RCC样本的DNA和RNA谱进行了首次综合分析。利用100K SNP定位阵列，我们构建了全基因组DNA拷贝数改变和杂合性缺失（LOH）区域图谱。我们由此确认了RCC的典型遗传特征，但也鉴定出了其他扩增区域（如在4号、11号、12号染色体上）、缺失区域（1号、9号、22号染色体）和LOH区域（1号、2号、9号、13号染色体）。同时，使用HG-U133 Plus 2.0阵列，我们鉴定了肿瘤样本与正常样本中差异表达的基因（DEGs）。结合基因组和转录组数据，我们在异常染色体区域鉴定出71个DEGs，并在扩增区域观察到上调基因占优势（37个DEGs中有27个）且有聚类趋势。对这些基因的功能注释揭示了一些已与RCC病理及其他癌症相关的基因，以及其他可能是新型肿瘤生物标志物的基因。
通过整合一组RCC样本的基因组和转录组图谱，我们鉴定出了DNA和RNA谱具有一致改变的特定基因组区域，并聚焦于DNA拷贝数增加的区域。由于扩增区域上调基因的转录调控可能归因于RCC的基因组改变，这些基因可能编码积极参与肿瘤起始和进展且在临床应用中有用的新型RCC生物标志物。
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