Abstract
PURPOSE: In renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data about the clinical course and additional molecular features in the context of contemporary systemic therapies remain limited. EXPERIMENTAL DESIGN: Clinical outcomes were evaluated in patients with RCC exhibiting merlin loss by IHC in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA). RESULTS: In the institutional cohort (n = 33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)-based regimens (n = 5) had numerically longer overall survival (24.5 vs. 16.5 months, P = 0.2) and progression-free survival (9.8 vs. 5 months, P = 0.5) compared with IO-based therapies (n = 18) though differences were not statistically significant. Genomic analysis (n = 17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage-response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n = 13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared with clear-cell RCC without NF2 inactivation (n = 529). CONCLUSIONS: Biallelic NF2 inactivation and merlin protein deficiency drive an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to IO highlights the need for molecularly tailored therapies.