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SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma
Purpose:
SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype.
Experimental Design:
We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial.
Results:
Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy.
Conclusions:
BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.
Insights
Alterations in the SWI/SNF (BAF) chromatin remodeling complex define a urothelial carcinoma subtype vulnerable to HDAC inhibitors. This discovery supports biomarker-driven trials and combination therapies for this cancer.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- SWI/SNF (BAF) chromatin remodeling complex alterations are frequent in urothelial carcinoma.
- No current therapeutic strategies target BAF alterations in this cancer.
Purpose of the Study:
- To determine if BAF alterations define a distinct, actionable urothelial carcinoma subtype.
- To investigate therapeutic vulnerabilities associated with BAF alterations.
Main Methods:
- Integrative genomic and transcriptomic analyses of urothelial carcinoma tumors (ORIEN and TCGA-BLCA cohorts).
- Mechanistic studies using RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition.
- Functional assessments in patient-derived xenograft organoids and cell lines.
Main Results:
- BAF alterations identified in ~50% of tumors, defining a chromatin-altered subtype with activated proliferation and altered metabolism.
- This subtype showed enrichment for HDAC inhibitor sensitivity and depletion of resistance signatures.
- HDAC inhibition led to chromatin remodeling and downregulation of key transcriptional networks, with enhanced sensitivity in ARID1A-mutated models.
Conclusions:
- BAF alterations create a chromatin-dependent state in urothelial carcinoma sensitive to HDAC inhibition.
- Findings support biomarker-enriched trials and combination strategies involving HDAC inhibitors for urothelial carcinoma.
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