Acquired SMARCA4 alterations: An uncommon contributor to cancer progression in lung adenocarcinomas

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 206; p. 108644
• Main Authors: Gagné, Andréanne, Alessi, Joao Victor M., Ricciuti, Biagio, Lamberti, Giuseppe, Awad, Mark M., Sholl, Lynette M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.08.2025
• Subjects: Acquired mutation; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Adult; Aged; Disease Progression; DNA Helicases - genetics; Female; Humans; Loss of function; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; Mutation; Non-small cell lung carcinoma; Nuclear Proteins - genetics; Retrospective Studies; SMARCA4; Transcription Factors - genetics; Acquired mutation; Non-small cell lung carcinoma; Loss of function; SMARCA4
• ISSN: 0169-5002; 1872-8332; 1872-8332
• DOI: 10.1016/j.lungcan.2025.108644

•Acquired SMARCA4 mutations during lung cancer progression are rare (2% incidence).•Patients were enriched for never-smoking females with targetable oncogenic drivers.•SMARCA4 loss often co-occurs with increased tumor mutational burden or APOBEC signatures.•Acquired SMARCA4 may drive phenotypic dedifferentiation and treatment resistance. SMARCA4 inactivation occurs in a subset of non-small cell lung carcinomas (NSCLC) and undifferentiated thoracic tumors, typically as an early clonal alteration in smokers. While rarely observed as an acquired event, the frequency and significance remain unclear. Given the aggressive nature of SMARCA4-deficient thoracic tumors, we hypothesized that SMARCA4 inactivation could represent a mechanism of progression and resistance following therapy. We report an index case of a patient with surgically-resected lung adenocarcinoma acquiring a SMARCA4 alteration at progression. We then conducted a retrospective analysis of 4154 patients with tumor genomic profiles, identifying NSCLC patients ≥ 2 sequencing tests. Clonally-related samples with pathogenic SMARCA4 mutations were further investigated alongside clinical and histopathologic features at each timepoint. Of 354 patients with ≥ 2 clonally-related tumor samples, seven (2.0 %) acquired a pathogenic SMARCA4 mutation following systemic therapy for advanced or recurrent disease. Median age was 60 years; 57 % were women and 71 % never smokers. Oncogenic drivers (EGFR, ERBB2, ROS1, KRAS, and BRAF) were identified in 6/7 (86 %) cases. All patients in the retrospective cohort received intervening systemic therapy, either tyrosine kinase inhibitors or chemoimmunotherapy. In 5/7 cases, SMARCA4 acquisition was observed in association with an increase in tumor mutational burden, often with APOBEC signatures. In 2/7 cases, SMARCA4 acquisition corresponded with worsening tumor grade and loss of TTF1/Napsin A expression. Acquired pathogenic SMARCA4 mutations are rare but may emerge under systemic therapy pressure, often alongside increased TMB. Morphologic changes accompanying the loss of SMARCA4 expression suggest pathobiological significance in select cases.