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 regarding the clinical course and additional molecular features in the context of contemporary systemic therapies remains limited.Methods: Clinical outcomes were evaluated in patients with RCC exhibiting merlin loss by immunohistochemistry 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 to 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 to clear cell RCC without NF2 inactivation (n=529). Conclusions: Biallelic NF2 inactivation and merlin protein deficiency drives an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to immunotherapy highlights the need for molecularly tailored therapies.
Yekedüz et al. (Mon,) studied this question.