Gagné Andréanne, Alessi Joao Victor M, Ricciuti Biagio, Lamberti Giuseppe, Awad Mark M, Sholl Lynette M
Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115, USA.
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston MA 02115, USA.
Lung Cancer. 2025 Aug;206:108644. doi: 10.1016/j.lungcan.2025.108644. Epub 2025 Jun 26.
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.
SMARCA4失活发生在一部分非小细胞肺癌（NSCLC）和未分化胸段肿瘤中，通常是吸烟者的早期克隆性改变。虽然作为获得性事件很少见，但其发生频率和意义仍不清楚。鉴于SMARCA4缺陷型胸段肿瘤具有侵袭性，我们推测SMARCA4失活可能代表治疗后进展和耐药的一种机制。
我们报告了一例手术切除的肺腺癌患者在疾病进展时发生SMARCA4改变的索引病例。然后，我们对4154例有肿瘤基因组图谱的患者进行了回顾性分析，确定了进行过≥2次测序检测的NSCLC患者。对具有致病性SMARCA4突变的克隆相关样本，同时结合每个时间点的临床和组织病理学特征进行了进一步研究。
在354例有≥2个克隆相关肿瘤样本的患者中，7例（2.0%）在晚期或复发性疾病的全身治疗后获得了致病性SMARCA4突变。中位年龄为60岁；57%为女性，71%为从不吸烟者。6/7（86%）的病例中发现了致癌驱动因素（EGFR、ERBB2、ROS1、KRAS和BRAF）。回顾性队列中的所有患者均接受了干预性全身治疗，包括酪氨酸激酶抑制剂或化疗免疫治疗。在5/7的病例中，观察到SMARCA4获得与肿瘤突变负担增加相关，通常伴有APOBEC特征。在2/7 的病例中，SMARCA4获得与肿瘤分级恶化和TTF1/Napsin A表达缺失相对应。
获得性致病性SMARCA4突变很少见，但可能在全身治疗压力下出现，通常伴随着肿瘤突变负荷增加。SMARCA4表达缺失伴随的形态学改变在某些病例中提示了病理生物学意义。
