Purpose: Tumor heterogeneity may represent a barrier to pre-operative genomic characterization by needle biopsy in clear cell renal cell carcinoma (ccRCC). The extent of heterogeneity in small renal tumors remains unknown. Therefore, we set out to evaluate heterogeneity in resected large and small renal tumors. Experimental Design: We conducted a study from 2013 through 2016, that evaluated 47 consecutive ccRCC tumors resected during radical or partial nephrectomy. Cases were designated as small (<4cm) and large (>7cm) tumors. Each tumor had 3 regions sampled. Copy number variation (CNV) was assessed and Gene expression analysis was performed to characterize the clear-cell A and B (ccA/ccB) profile and the Cell Cycle Progression (CCP) score. Genomic heterogeneity between 3 regions was evaluated using CNV subclonal events, regional expression profiles, and correlation between gene expression. Results: 23 small and 24 large tumors were analyzed. Total CNVs and subclonal CNVs events were less frequent in small tumors (p<0.001). Significant gene expression heterogeneity was observed for both CCP scores and ccA/ccB classifications. Larger tumors had more variance in CCP scores (p=0.026). The distribution of ccA/ccB differed between small and large tumors with mixed ccA/ccB tumors occurring more frequently in the larger tumors (p=0.024). Analysis of 5 mixed tumors (with both ccA/ccB regions) demonstrated the more aggressive ccB phenotype had greater CNV events (p=0.014). Conclusions: Small renal tumors have much less genomic complexity and fewer subclonal events. Pre-treatment genomic characterization with single needle biopsy in small tumors may be useful to assess biologic potential and may influence therapy.
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