EVALUATION OF GENOMIC AND TRANSCRIPTOMIC ALTERATIONS AND INTRATUMORAL HETEROGENEITY IN SMALL RENAL MASSES UPSTAGED TO PATHOLOGIC T3A CLEAR CELL RENAL CELL CARCINOMA

Introduction For patients with clinical T1 renal masses, active surveillance is becoming an increasingly popular management option instead of surgical resection or ablation. However, we lack effective prognostic biomarkers to identify patients with high-risk disease. Additionally, the presence of intratumoral heterogeneity in renal cell carcinoma (RCC) may impact our ability to use a genomic biomarker on renal mass biopsy (RMB) tissue. This study seeks to evaluate genomic and transcriptomic features associated with conversion from clinical T1 to pathologic T3 disease and characterize the extent of intratumoral heterogeneity. Methods From October 2018–June 2022, patients with new clinical T1 kidney tumors were enrolled onto GRADE-SRM (Genomic Risk Assessment and Decisional Evaluation for Small Renal Masses), a comparative, non-randomized hybrid trial assessing decision-making experience and cancer genomics. Tissue from surgery (including multifocal sampling), RMB, and germline DNA was obtained. Targeted exon sequencing was performed using UNCseq v10.2 platform and variants were filtered using standard criteria. Intratumoral heterogeneity was measured by mutation concordance, defined as percent of mutations in nephrectomy specimen also identified in multifocal sampling. RNA sequencing was performed using Illumina TruSeq Stranded mRNAseq with standard data processing. Results Of 70 patients with clear cell RCC who underwent surgery, 10 tumors converted from cT1b to pT3a based on surgical pathology and were compared to 16 cT1b tumors who remained pT1b. pT3a tumors demonstrated similar number of variants compared to pT1b tumors (7.4 vs 5.3, p=0.07) and similar levels of intratumoral heterogeneity (mutation concordance 66% vs 68%, p=0.89). However, pT3a tumors demonstrated a higher percentage with SETD2 mutations compared to pT1b tumors (30% vs 5%). Transcriptomic analysis identified 51 genes that were differentially expressed between pT1b and pT3a tumors. Conclusions This study identifies genomic and transcriptomic differences between cT1b tumors that remain pT1b versus those that convert to pT3a. These results highlight potential alterations for use as prognostic biomarkers to risk stratify patients and guide decisions regarding active surveillance vs treatment. Future research will focus on evaluating whether these alterations can be identified on prospectively collected standard-of-care RMB specimens.