Evidence for Polyclonal Origin of Multifocal Clear Cell Renal Cell Carcinoma

Purpose: Renal cell carcinomas are often multifocal. We investigated the genomic signatures of multifocal clear cell renal cell carcinoma to determine whether multiple tumors in the same kidney bear a clonal relationship to one another. Experimental Design: A total of 62 tumors from 26 patients who underwent radical nephrectomy were examined. All patients had multiple separate clear cell renal carcinomas. Loss of heterozygosity analyses were done using five microsatellite polymorphic markers that represent putative tumor suppressor genes on chromosome 3p14 (D3S1300), 7q31 (D7S522), 8p22 (D8S261), 9p21 (D9S171), and 17p13 (TP53). X chromosome inactivation analyses were also done on the renal tumors from the 10 female patients. Chromosome 3p deletion status was determined by dual color interphase fluorescence in situ hybridization analysis in all tumors. Results: Nineteen of the 26 (73%) patients with multifocal clear cell renal cell carcinoma showed allelic loss in at least 1 of 5 microsatellite loci in separate tumors analyzed. A disconcordant pattern of allelic loss between coexisting kidney tumors was observed in 7 cases. Six cases showed discordant 3p deletion patterns by dual color interphase fluorescence in situ hybridization analysis. Of the eight informative female cases studied by X chromosome inactivation, one showed a discordant nonrandom pattern of X chromosome inactivation. Overall, evidence of independent origin of the multifocal renal tumors was observed in 12 of 26 cases (46%). Conclusions: Our data suggest that in a significant number of cases of multifocal clear cell renal cell carcinoma, the spatially separate tumors are of different clonal origin and arise independently.