Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 20; pp. 5273 - 5284
• Main Authors: GIRGIS, Andrew H, LAKOVLEV, Vladimir V, PASIC, Maria, YOUSEF, George M, BEHESHTI, Ben, BAYANI, Jane, SQUIRE, Jeremy A, BUI, Anna, MANKARUOS, Marina, YOUSSEF, Youssef, KHALIL, Bishoy, KHELLA, Heba
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2012
• Subjects: Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Chromosome Mapping; Gene Dosage; Genome, Human; Humans; In Situ Hybridization, Fluorescence; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Nucleic Acid Hybridization; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Tumors; Tumors of the urinary system; Kidney disease; Clear cell; Urinary system disease; Carcinoma; Analysis; Kidney cancer; Biological marker; Genetics; Grawitz tumor; Malignant tumor; Genome; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-0656

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.