Mayo Clinic proceedings · 2026
Utility of Next-Generation Sequencing in Renal Neoplasia, Including Tumors With Clear Cytoplasm and Rare Phenotypes (ELOC/MITF Alterations and Mismatch Repair Deficiency).
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McCarthy Michael, Wojcik Antonina A, Barr Fritcher Emily G, Tekin Burak, Shen Wei, Al-Kateb Hussam, Dasari Surendra, Lucas Peter C, Ebare Kingsley, Reynolds Jordan P, Stanton Melissa L, Raghunathan Aditya, Whaley Rumeal D, Erickson Lori A, Hernandez Loren Herrera, Jimenez Rafael E, Costello Brian A, Potretzke Aaron, Boorjian Stephen A, Sharma Vidit, Leibovich Bradley C, Cheville John C, Kipp Benjamin R, Gupta Sounak
Аннотация
OBJECTIVE: To define the clinical utility of next-generation sequencing (NGS) of renal tumors, including carbonic anhydrase 9-positive renal neoplasia with clear cell features (ccRCN) that include ELOC (for expansion of gene symbols, use search tool at www.genenames.org) and MTOR/TSC1/TSC2-mutated renal cell carcinoma (RCC) with fibromyomatous stroma (ELOC-RCCfms and M/TSC-RCCfms, respectively), as these tumors often have overlapping features.
PATIENTS AND METHODS: Renal tumors (n=234) diagnosed between August 1, 2021, and June 15, 2025, were submitted for genomic profiling using Clinical Laboratory Improvement Amendments-validated 515-gene (n=30), 30-gene (n=175), and smaller (<5 gene, n=29) next-generation sequencing panels. Available histologic and NGS data was reviewed to render a final integrated diagnosis and determine clinical utility.
RESULTS: Next-generation sequencing was requested solely for diagnostic indications in most cases (209 of 234 [89%]), with 66% of cases (154 of 234) showing a clinically impactful genomic profile. The highest utility was among ccRCN and high-grade RCC/RCC, type not otherwise specified (NOS) in which only 8 of 79 (10%) and 17 of 57 (30%) remained unclassifiable, respectively. Some rare phenotypes included variants associated with hereditary disease, uncommon presentations, multiple driver alterations, mismatch repair deficiency (n=3), and rare MITF p.E318K alterations (n=3). The cohort of ccRCN included 12 ELOC-RCCfms (p.Y79C/S: 9 of 12; p.A100E, 2 of 12; p.L104Q: 1 of 12). GPNMB was expressed in M/TSC-RCCfms (10 of 10, 100%) and lacked appreciable expression in most ccRCN tested (n=25), including ELOC-RCCfms.
CONCLUSION: Next-generation sequencing-based molecular profiling had clinical utility in two-thirds of patients, and the greatest benefit was within the broad category of ccRCN. Our results suggest that GPNMB expression was helpful in separating ELOC-RCCfms from M/TSC-RCCfms. Other benefits of NGS include subtyping high-grade RCC/RCC type not otherwise specified and identification of rare phenotypes.
PATIENTS AND METHODS: Renal tumors (n=234) diagnosed between August 1, 2021, and June 15, 2025, were submitted for genomic profiling using Clinical Laboratory Improvement Amendments-validated 515-gene (n=30), 30-gene (n=175), and smaller (<5 gene, n=29) next-generation sequencing panels. Available histologic and NGS data was reviewed to render a final integrated diagnosis and determine clinical utility.
RESULTS: Next-generation sequencing was requested solely for diagnostic indications in most cases (209 of 234 [89%]), with 66% of cases (154 of 234) showing a clinically impactful genomic profile. The highest utility was among ccRCN and high-grade RCC/RCC, type not otherwise specified (NOS) in which only 8 of 79 (10%) and 17 of 57 (30%) remained unclassifiable, respectively. Some rare phenotypes included variants associated with hereditary disease, uncommon presentations, multiple driver alterations, mismatch repair deficiency (n=3), and rare MITF p.E318K alterations (n=3). The cohort of ccRCN included 12 ELOC-RCCfms (p.Y79C/S: 9 of 12; p.A100E, 2 of 12; p.L104Q: 1 of 12). GPNMB was expressed in M/TSC-RCCfms (10 of 10, 100%) and lacked appreciable expression in most ccRCN tested (n=25), including ELOC-RCCfms.
CONCLUSION: Next-generation sequencing-based molecular profiling had clinical utility in two-thirds of patients, and the greatest benefit was within the broad category of ccRCN. Our results suggest that GPNMB expression was helpful in separating ELOC-RCCfms from M/TSC-RCCfms. Other benefits of NGS include subtyping high-grade RCC/RCC type not otherwise specified and identification of rare phenotypes.