Genomic Heterogeneity and the Small Renal Mass

Tumor heterogeneity may represent a barrier to pre-operative genomic characterization by needle biopsy in renal cell carcinoma (RCC). We evaluate heterogeneity in resected small renal masses (SRM) to provide insights into the limitations of pre-treatment biopsy.

23 small (cT1a) and 24 large (cT2+) clear cell RCC had 3+ regions sampled >1 cm apart at time of nephrectomy. Copy number variation (CNV) of driver alterations was assessed using an Illumina Human CytoSNP12 array. Gene expression analysis was performed with a custom Nanostring digital RT-PCR array to characterize previously described clear cell A and B (ccA/ccB) profile and Cell Cycle Progression (CCP) score.

Large tumors more frequently had losses of 14q24, 2q37, and 9p21 (p<0.05). Total CNVs were much less frequent in small tumors (median 2.5 vs 6.5, p=0.006). Subclonal CNV events were less common in small tumors (median 0 vs 3, p=0.002). Significant gene expression heterogeneity was observed for both CCP and ccA/B classifications. Larger tumors had significantly more variance in CCP scores (p=0.026). ccA/B scores differed between small and large tumors with mixed ccA/B tumors occurring more frequently in the larger tumors (p=0.048). Analysis of 5 mixed tumors that had CNV events demonstrated the more aggressive B phenotype had greater CNV events (median 7 vs 2, p=0.011).

We present the largest cohort of multiregion sampling in clear cell RCC. Small renal tumors have much less genomic complexity and less subclonal events. We demonstrate that ccA/ccB profiles can vary within the primary tumor, however this is much less frequent in small renal tumors. Our findings support an ongoing small renal mass trial where pre-treatment genomic characterization is performed based on a single biopsy. However, single biopsies for large tumors might be less useful due to greater heterogeneity.