Multi-level whole genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma
Menée sur 159 échantillons de carcinome rénal à cellules claires et sur des données issues du Cancer Genome Atlas, cette étude identifie des anomalies du nombre de copies et de la méthylation de gènes en association avec la survie des patients
Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. We performed an integrated analysis of copy-number, gene expression (mRNA, miRNA), protein expression and methylation changes in clear cell renal cell carcinoma (ccRCC). We utilized a step-wise approach to identify the most significant copy-number aberrations 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 copy number aberration (CNA) compared to tumors without aberration. We also identified genes located in peak copy-number aberrations 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, like 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 RCC. 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 copy-number aberrations in conjuction with methylation changes on the expression of cancer-related genes, miRNAs and proteins and their influence on patient survival.
Cancer Research , résumé, 2012