食管腺癌中 SWI/SNF-ATP 酶亚基成员 SMARCF1（ARID1A）、SMARCA2（BRM）、SMARCA4（BRG1）和 SMARCB1（INI1）的缺失。

Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma.

机构信息

Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.

出版信息

BMC Cancer. 2020 Jan 6;20(1):12. doi: 10.1186/s12885-019-6425-3.

DOI:10.1186/s12885-019-6425-3

PMID:31906887

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6945480/

Abstract

BACKGROUND

The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC).

METHODS

We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data.

RESULTS

Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2-139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7-19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2).

CONCLUSION

Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

摘要

背景

SWI/SNF 复合物是一种重要的染色质重塑因子，在癌症中经常失调，估计突变频率为 20%。ARID1A 是最常突变的亚基基因。几乎没有人知道 SWI/SNF 复合物的其他熟悉成员，SMARCA2（BRM）、SMARCA4（BRG1）和 SMARCB1（INI1），在食管腺癌（EAC）中的情况。

方法

我们分析了 685 例 EAC 患者的大型队列。我们使用四种不同的抗体通过免疫组织化学检测 ARID1A、BRM、BRG1 和 INI1 的蛋白缺失，并将这些发现与分子和临床数据相关联。

结果

在 10.4%、3.4%、9.9%和 2%的 EAC 中观察到 ARID1A、BRG1、BRM 和 INI1 的缺失。我们发现 9.9%的患者存在 ARID1A 和 BRM 共存的蛋白缺失，2.2%的患者存在 ARID1A 和 BRG1 的共存蛋白缺失。与 ARID1A 阳性肿瘤相比，ARID1A 和 TP53 野生型 EAC 患者的 ARID1A 和 BRM 缺失的总体生存期更短[中位总生存期为 60.1 个月（95%CI 1.2-139.9 个月）]，ARIDA-1A 表达患者为 26.2 个月（95%CI 3.7-19.1 个月），差异具有统计学意义（p=0.044）。ARID1A 和 TP53 缺失或表达的肿瘤的生存无差异。只有一个肿瘤表现出高微卫星不稳定性（MSI-H），同时伴有 ARID1A 缺失。所有其他 ARID1A 缺失-EAC 均为微卫星稳定（MSS）。SWI/SNF 复合物改变和同时扩增不同基因（PIK3CA、KRAS、c-MYC、MET、GATA6、ERBB2）之间没有预测相关性。

结论

我们的工作首次描述了食管腺癌中大量腺癌细胞中一种 SWI/SNF ATP 酶亚基蛋白的缺失。有几篇论文讨论了针对 SWI/SNF 复合物功能丧失的肿瘤的可能治疗干预措施，如 PARP 抑制剂或 PI3K 和 AKT 抑制剂。未来的研究将需要表明 SWI/SNF 复合物缺陷型 EAC 是否可能受益于个体化治疗。