Abstract
BackgroundClear 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.ResultsWe 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.ConclusionBy 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.
Highlights
Clear cell renal carcinoma (RCC) is the most common and invasive adult renal cancer
These results illustrate a great heterogeneity in copy number alterations (CNAs) profile among the 27 tumor samples
To narrow down the number of candidate genes to those whose altered expression level was attributable to underlying DNA alterations, genomic and transcriptomic data were combined at genome level. This permitted us to identify specific chromosomal regions with concordant alterations in DNA and RNA profiles. These regions are of particular interest since they contain genes which, being transcriptionally modulated due to genomic alterations, could be novel RCC constitutive markers actively involved in tumor initiation and progression and useful in clinical applications
Summary
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. Clear cell (or conventional) renal cell carcinoma (RCC) accounts for about 85% of all primary kidney malignancies and, familial forms of RCC exist, the disease is more often sporadic[1] This pathology is associated with genetic alterations affecting particular chromosomes [2,3]. Duplications of chromosomes 5q and 7 and deletions on chromosomes 6q, 8p, 9p and 14q are other typical chromosomal abnormalities Another recurrent RCC genetic feature is a particular pattern of loss of heterozygosity (LOH), i.e. the change from a heterozygous genotype in a normal sample to a homozygous one in a tumor, with a high frequency of allelic imbalances on chromosome 3p in conjunction with 6q, 8p, 9p and q, and 14q [5]. Many studies have profiled transcriptional patterns in RCC samples, but a univocally accepted gene expression signature is lacking [6]
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