Abstract：
SMARCA4 mutation has emerged as a marker of poor prognosis in lung cancer and has potential predictive value in cancer treatment, but recommendations for which patients require its investigation are lacking. We comprehensively studied SMARCA4 alterations and the clinicopathological significance in a large cohort of immunohistochemically-subtyped non-small cell lung cancer (NSCLC). A total of 1416 patients was studied for the presence of SMARCA4 deficiency by immunohistochemistry (IHC). Thereafter, comprehensive sequencing of tumours was performed for 397 of these patients to study the mutational spectrum of SWI/SNF and SMARCA4 aberrations. IHC evidence of SMARCA4 deficiency was found in 2.9% of NSCLC. Of the sequenced tumours, 38.3% showed aberration in SWI/SNF complex, and 9.3% had SMARCA4 mutations. Strikingly, SMARCA4 aberrations were much more prevalent in large cell carcinoma (LCC) than other histological tumour subtypes. SMARCA4-deficient and SMARCA4-mutated tumours accounted for 40.5% and 51.4% of all LCC, respectively. Multivariable analyses confirmed SMARCA4 mutation was an independent prognostic factor in lung cancer. The immunophenotype of a subset of these tumours frequently showed TTF1 negativity and HepPAR1 positivity. SMARCA4 mutation or its deficiency was associated with positive smoking history and poor prognosis. It also demonstrated mutual exclusion with EGFR mutation. Taken together, the high incidence of SMARCA4 aberrations in LCC may indicate its diagnostic and prognostic value. Our study established the necessity of SMARCA4 IHC in the identification of SMARCA4-aberrant tumours, and this may be of particular importance in LCC and tumours without known driver events.
摘要：
SMARCA4突变已成为肺癌预后不良的标志物，在癌症治疗中具有潜在的预测价值。但是缺乏患者需要进行调查的建议。我们在免疫组织化学亚型非小细胞肺癌（NSCLC）的大型队列中全面研究了SMARCA4改变及其临床病理意义。通过免疫组织化学（IHC）研究了1416例患者是否存在SMARCA4缺乏症。此后,对这些患者中的397例进行了肿瘤综合测序,以研究SWI/SNF和SMARCA4畸变的突变谱.在2.9％的NSCLC中发现了SMARCA4缺乏的IHC证据。在测序的肿瘤中，38.3%的SWI/SNF复合物出现畸变,9.3%有SMARCA4突变。引人注目的是，SMARCA4畸变在大细胞癌（LCC）中比其他组织学肿瘤亚型更为普遍。SMARCA4缺陷和SMARCA4突变的肿瘤占所有LCC的40.5%和51.4%，分别。多变量分析证实SMARCA4突变是肺癌的独立预后因素。这些肿瘤的一个子集的免疫表型经常显示TTF1阴性和HepPAR1阳性。SMARCA4突变或其缺陷与阳性吸烟史和不良预后相关。它还证明了与EGFR突变的相互排斥。一起来看,SMARCA4异常在LCC中的高发生率可能表明其诊断和预后价值.我们的研究确立了SMARCA4IHC在识别SMARCA4异常肿瘤中的必要性，这在没有已知驱动事件的LCC和肿瘤中可能特别重要。
