Integrative genomic landscape of germline exome alterations in renal cell carcinoma, unclassified with medullary phenotype.

Abstract

524 Background: SMARCB1-deficient Renal Medullary Carcinoma (RMC) is a rare non-clear cell renal cell carcinoma predominantly affecting children and young adults of African descent with sickle hemoglobinopathies, most commonly sickle cell trait due to germline mutations in the HBB gene. SMARCB1-deficient renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP) is a rare RMC subtype not associated with sickle hemoglobinopathies. Aside from confirming sickle hemoglobinopathies, germline testing is not established for RMC or RCCU-MP, and RCCU-MP germline risk factors are unknown. We herein report the largest assembled series of RMC and RCCU-MP germline profiles reported to date. Methods: We retrospectively analyzed germline whole-exome sequencing (WES) from patients with RCCU-MP (n = 11), RMC (n = 23), clear-cell RCC (ccRCC; n = 12), and chromophobe RCC (chRCC; n = 11). HBB sickle hemoglobinopathy gene mutations served as internal controls for RMC. To mitigate ancestry confounding, we compared findings with independent cohorts of African American patients with RCC (n = 11), prostate (n = 7), and urothelial carcinomas(n = 5). Clinical and demographic variables were abstracted from the electronic medical record. Associations between genomic features and clinicodemographic variables were evaluated. Survival analyses were performed using Kaplan-Meier methodology and Cox proportional hazards models. Results: Patients with both RCCU-MP and RMC were young (median age 35 and 28 years, respectively) and enriched for advanced stage at testing. Median overall survival (OS) was shortest for RMC (1.7 years), followed by RCCU-MP (1.8), chRCC (2.9), and ccRCC (4.7). Global germline mutational burden showed no tumor-type–specific enrichment. However, RCCU-MP demonstrated a distinct excess of homologous recombination repair (HRR) pathway protein truncating variants (PTVs), most notably in ATM and RAD50, versus RMC, ccRCC, and chRCC. In contrast, RMC showed the expected enrichment of HBB. No additional hemoglobinopathy-related germline variants beyond HBB were identified in any group. Conclusions: Germline HRR-pathway disruption is enriched in SMARCB1-deficient RCCU-MP lacking sickle hemoglobinopathies, whereas canonical RMC remains defined by HBB variants without broader hemoglobinopathy signals. These data support targeted referral to genetics and incorporation of HRR testing in RCCU-MP work-ups, and motivate mechanistic and therapeutic studies of DNA-damage response biology in this medullary phenotype.