Department of Laboratory Medicine, and the Keenan Research Centre in the Li Ka Shing Knowledge Institute St. Michael's Hospital, Toronto, Canada.
Cancer Res. 2012 Oct 15;72(20):5273-84. doi: 10.1158/0008-5472.CAN-12-0656. Epub 2012 Aug 27.
Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. We conducted an integrated analysis of copy number, gene expression (mRNA and miRNA), protein expression, and methylation changes in clear cell renal cell carcinoma (ccRCC). We used a stepwise approach to identify the most significant copy number aberrations (CNA) and identified regions of peak and broad copy number gain and loss, including peak gains (3q21, 5q32, 5q34-q35, 7p11, 7q21, 8q24, 11q13, and 12q14) and deletions (1p36, 2q34-q37, 3p25, 4q33-q35, 6q23-q27, and 9p21). These regions harbor novel tumor-related genes and miRNAs not previously reported in renal carcinoma. Integration of genome-wide expression data and gene set enrichment analysis revealed 75 gene sets significantly altered in tumors with CNAs compared with tumors without aberration. We also identified genes located in peak CNAs with concordant methylation changes (hypomethylated in copy number gains such as STC2 and CCND1 and hypermethylated in deletions such as CLCNKB, VHL, and CDKN2A/2B). For other genes, such as CA9, expression represents the net outcome of opposing forces (deletion and hypomethylation) that also significantly influences patient survival. We also validated the prognostic value of miRNA let-7i in RCCs. miR-138, located in chromosome 3p deletion, was also found to have suppressive effects on tumor proliferation and migration abilities. Our findings provide a significant advance in the delineation of the ccRCC genome by better defining the impact of CNAs in conjunction with methylation changes on the expression of cancer-related genes, miRNAs, and proteins and their influence on patient survival.
肾细胞癌 (RCC) 是肾脏最常见的肿瘤。我们对透明细胞肾细胞癌 (ccRCC) 的拷贝数、基因表达 (mRNA 和 miRNA)、蛋白质表达和甲基化变化进行了综合分析。我们采用逐步方法来确定最显著的拷贝数异常 (CNA)，并确定了峰值和广泛的拷贝数增益和丢失区域，包括峰值增益 (3q21、5q32、5q34-q35、7p11、7q21、8q24、11q13 和 12q14) 和缺失 (1p36、2q34-q37、3p25、4q33-q35、6q23-q27 和 9p21)。这些区域包含以前在肾癌中未报道过的新的肿瘤相关基因和 miRNA。全基因组表达数据的整合和基因集富集分析显示，与无异常的肿瘤相比，CNA 肿瘤中有 75 个基因集显著改变。我们还鉴定了与 CNA 中一致的甲基化变化相关的基因 (如 STC2 和 CCND1 中拷贝数增益导致低甲基化，而 CLCNKB、VHL 和 CDKN2A/2B 中缺失导致高甲基化)。对于其他基因，如 CA9，其表达代表了相反力量(缺失和低甲基化)的净结果，这也显著影响患者的生存。我们还验证了 miRNA let-7i 在 RCC 中的预后价值。位于 3p 缺失的 miR-138 也被发现对肿瘤增殖和迁移能力具有抑制作用。我们的研究结果通过更好地定义 CNA 与甲基化变化对癌症相关基因、miRNA 和蛋白质表达的影响及其对患者生存的影响，为描绘 ccRCC 基因组提供了重要进展。
