Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density...

Genetic aberrations are crucial in renal tumor progression. In this study, we describe loss of heterozygosity (LOH) and DNA-copy number abnormalities in clear cell renal cell carcinoma (cc-RCC) discovered by genome-wide single nucleotide polymorphism (SNP) arrays. Genomic DNA from tumor and normal tissue of 22 human cc-RCCs was analyzed on the Affymetrix GeneChip Human Mapping 10K Array. The array data were validated by quantitative polymerase chain reaction and immunohistochemistry. Reduced DNA copy numbers were detected on chromosomal arm 3p in 91%, on chromosome 9 in 32%, and on chromosomal arm 14q in 36% of the tumors. Gains were detected on chromosomal arm 5q in 45% and on chromosome 7 in 32% of the tumors. Copy number abnormalities were found not only in FHIT and VHL loci, known to be involved in renal carcinogenesis, but also in regions containing putative new tumor suppressor genes or oncogenes. In addition, microdeletions were detected on chromosomes 1 and 6 in genes with unknown impact on renal carcinogenesis. In validation experiments, abnormal protein expression of FOXP1 (on 3p) was found in 90% of tumors (concordance with SNP array data in 85%). As assessed by quantitative polymerase chain reaction, PARK2 and PACRG were down-regulated in 57% and 100%, respectively, and CSF1R was up-regulated in 69% of the cc-RCC cases (concordance with SNP array data in 57%, 33%, and 38%). Genome-wide SNP array analysis not only confirmed previously described large chromosomal aberrations but also detected novel microdeletions in genes potentially involved in tumor genesis of cc-RCC.