Samuel A. Funt

Purpose:The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. Experimental Design:We analyzed 68,920 tumor–normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. We curated oncogenic or likely oncogenic SMARCA4 alterations using OncoKB and classified them based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. Results:SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non–small cell lung cancer (7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including 1 who attained a complete response. Conclusions:SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.

Purpose: The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. Experimental Design: We analyzed 68,920 tumor–normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. We curated oncogenic or likely oncogenic SMARCA4 alterations using OncoKB and classified them based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. Results: SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non–small cell lung cancer (7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including 1 who attained a complete response. Conclusions: SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.

Background: Urothelial cancer typically affects older adults, yet early-onset urothelial cancer (age 45 years and younger) cases are rising and remain poorly characterized. We hypothesized that early-onset urothelial cancer exhibits distinct clinical and genomic features that reflect a different biological etiology from standard-onset urothelial cancer. Methods: We compared clinical, pathologic, and genomic characteristics of patients with early-onset urothelial cancer vs standard-onset urothelial cancer evaluated at Memorial Sloan Kettering Cancer Center from 2000 through 2024. Clinical data included 9221 patients, with tumor and germline genomic profiling by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay in 2753 patients. Results: Early-onset urothelial cancer accounted for 335 of 9221 (3.6%) patients. Early-onset urothelial cancer patients were more likely never-smokers (43% vs 26%, P < .001), female (30% vs 25%, P = .034), and of Asian race (7.4% vs 3.1%, P < .001). Early-onset urothelial cancer tumors were more often low-grade (41% vs 23%, P < .001) and of pure nonurothelial histology (4.0% vs 1.7%, P = .003). Early-onset urothelial cancer showed marked enrichment for HRAS mutations, independent of histologic subtype, and HRAS-mutated tumors had reduced APOBEC-associated mutation signatures. Germline pathogenic variants were detected in 21.0% of early-onset vs 17.2% of standard-onset urothelial cancer patients (P = .43), driven mostly by mismatch repair and MUTYH gene alterations. Rare cases of somatic mosaicism in HRAS and ERCC2 were observed in patients with very early-onset disease. Conclusions: Early-onset urothelial cancer represents a biologically distinct subset characterized by HRAS-driven oncogenesis, reduced APOBEC mutagenesis, frequent germline variants, and, rarely, somatic mosaicism. These findings suggest developmental or genetic mechanisms underlying early-onset urothelial cancer and supporting age- and biology-informed approaches to risk assessment, genetic counseling, and targeted therapy development.

Plasma cell-free DNA sequencing data

Representativeness of Study Participants