Abstract 1123: Comprehensive molecular characterization reveals hallmarks and therapeutic insights of collecting duct carcinoma

Abstract Purpose: Collecting duct carcinoma (CDC) is a rare and aggressive subtype of renal carcinoma, posing significant challenges in diagnosis and treatment. Current treatment relies on platinum-based chemotherapy, yet clinical outcomes remain poor. While targeted therapies and immune checkpoint inhibitors (ICIs) show promise in clear-cell renal cell carcinoma (ccRCC), they have not been evaluated in CDC, and their efficacy remains speculative. This underscores a pressing need for personalized treatment approaches, driven by an in-depth molecular understanding of the disease. Experimental Design: We conducted a comprehensive molecular characterization of 22 CDC cases using whole-exome sequencing, RNA-seq, and DNA methylation profiling. Renal medullary carcinoma, ccRCC, type 2 papillary RCC, and chromophobe RCC were included as comparators. To verify mutations of interest, we retrieved 25 CDC samples from GENIE (v15.0). We also assessed the association of genomic alterations with response to ICIs using data from the BIONIKK trial (NCT02960906) and the published CheckMate (-009, -010, -025) trials. Results: We identified frequent mutations in NF2 (20%), LZTR1 (20%), and SMARCB1 (10%), all located on chromosome 22q, along with 22q copy number loss (52%). Mutations in NF2, SAV1, and WWC1—key components of the Hippo signaling pathway—were observed, implicating its disruption (33%) and leading to overexpression of the YAP signature. Notably, a mutually exclusive pattern between DNA damage-related (DDR) mutations (33%) and 22q loss was observed. Transcriptomic analysis highlighted a cell cycle and immune cell enrichment signature in CDC, distinct from other RCC comparators. TME deconvolution revealed two CDC phenotypes tightly associated with genomic alterations. The immune-hot CDC was characterized by enrichment of CD8 T cells, B cells, and tertiary lymphoid structure signatures, and was enriched in DDR mutations. In contrast, the immune-cold CDC was marked by 22q loss and overexpression of the YAP signature. Furthermore, post-hoc analyses using BIONIKK and CheckMate data demonstrated that combining 22q loss and DDR mutations improves the precision of ICI response predictions. We also found a correlation between 22q loss and a CpG Island Methylator Phenotype (CIMP) pattern in CDC, which resembles the aggressive, immune-evasive CIMP subgroup observed in type 2 papillary RCC. Conclusions: Our comprehensive characterization broadens the molecular understanding of CDC, revealing actionable vulnerabilities such as DDR mutations for immunotherapy and YAP activation for targeted interventions. These findings redefine CDC’s therapeutic possibilities, offering a roadmap for precision oncology in this rare malignancy. Citation Format: Xiaofan Lu, Wenxuan Cheng, Nassim Tawanaie Pour Sedehi, Li Xu, Xiaoping Su, Roger Mouawad, Nizar M. Tannir, Gabriel G. Malouf. Comprehensive molecular characterization reveals hallmarks and therapeutic insights of collecting duct carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1123.