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Genomic Heterogeneity and the Small Renal Mass
Daiki Ueno, MD¹, Marta Boeke, PhD¹, Jamil S. Syed, MD¹, Kevin A. Nguyen, MS¹, Patrick Macgillivray, MD², Adebowale Adeniran, MD³, Peter Humphrey, MD PhD³, Yuval Kluger, PhD³, Zhonzhi Liu, PhD³, Harriet Kluger, MD⁴, Brian Shuch, MD¹.
¹Yale Department of Urology, New Haven, CT, USA, ²Yale Department of Molecular Biophysics and Biochemistry, New Haven, CT, USA, ³Yale Department of Pathology, New Haven, CT, USA, ⁴Yale Department of Medicine, New Haven, CT, USA.

BACKGROUND: Pre-treatment genomic characterization of the small renal mass is now feasible, however extensive tumor heterogeneity in renal cell carcinoma (RCC) may represent a barrier to widespread adoption. This concept emerged from multi-site assessment of large renal masses. We set out to evaluate genomic heterogeneity in resected small and large renal tumors to provide further insight into the limitations of this approach. METHODS: A consecutive series (n=100) of nephrectomy specimens had 3+ regions sampled >1 cm apart at the time of gross pathologic exam. A total of 47 small (cT1a) and large (cT2+) clear cell tumors were selected for evaluation. DNA was extracted for copy number variation (CNV) of common driver alterations from the Cancer Genomic Atlas (TCGA) using an Illumina Human CytoSNP12 array. Gene expression analysis was performed with a custom Nanostring digital RT-PCR array and analyzed with nSolverAnalysis Software to characterize ccA vs ccB profiles as well as the Prolaris Cell Cycle Progression (CCP) score. Total and subclonal CNVs, CCP score, and ccA/B classification was assessed by tumor, size grouping, and individual region.
RESULTS: A total of 23 small (cT1a) and 24 large (cT2+) tumors were analyzed. CNV and RT-PCR analysis was performed on 44 and 42 tumors, respectfully, 36 of which had successful analysis of all three regions with both modalities. Overall CNV profiles were similar to the TCGA with 3p25 loss and 5q35 gain being the most common events. Large tumors more frequently had loss of 14q24 and 9p21 (p<0.05), both known to influence prognosis. Total CNVs were much less frequent in smaller tumors (median 2.5 vs 6.5, p=0.006). Subclonal CNV events were also less common in small tumors (median 0 vs 3, p=0.002). Different CNV patterns emerged with specific alterations appearing more truncal and others more branch events in tumor evolution. 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 cc A/B tumors being more frequently in the larger cohort (23.8 vs 4.7%, overall 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). CONCLUSIONS: We present the largest cohort of multiregion sampling in clear cell RCC. Small renal tumors have much less genomic complexity and fewer subclonal events when compared to large tumors. For the first time, we demonstrate that ccA/ccB profiles can vary between tumors 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.

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