Weihai Municipal Hospital, Shandong University, Weihai, China.
Department of Oncology, Shouguang People's Hospital, Weifang, China.
Cancer Med. 2023 Aug;12(16):16716-16733. doi: 10.1002/cam4.6294. Epub 2023 Jun 27.
AT-rich interaction domain 1A (ARID1A) is an essential subunit of the switch/sucrose non-fermentable chromatin remodeling complex and is considered to be a tumor suppressor. The Cancer Genome Atlas (TCGA) molecular classification has deepened our understanding of gastric cancer at the molecular level. This study explored the significance of ARID1A expression in TCGA subtypes of gastric adenocarcinoma.
We collected 1248 postoperative patients with gastric adenocarcinoma, constructed tissue microarrays, performed immunohistochemistry for ARID1A, and obtained correlations between ARID1A and clinicopathological variables. We then carried out the prognostic analysis of ARID1A in TCGA subtypes. Finally, we screened patients by random sampling and propensity score matching method and performed multiplex immunofluorescence to explore the effects of ARID1A on CD4, CD8, and PD-L1 expression in TCGA subtypes.
Seven variables independently associated with ARID1A were screened out: mismatch repair proteins, PD-L1, T stage, differentiation status, p53, E-cadherin, and EBER. The independent prognostic variables in the genomically stable (GS) subtype were N stage, M stage, T stage, chemotherapy, size, and ARID1A. PD-L1 expression was higher in the ARID1A negative group than in the ARID1A positive group in all TCGA subgroups. CD4 showed higher expression in the ARID1A negative group in most subtypes, while CD8 did not show the difference in most subtypes. When ARID1A was negative, PD-L1 expression was positively correlated with CD4/CD8 expression; while when ARID1A was positive, this correlation disappeared.
The negative expression of ARID1A occurred more frequently in the Epstein-Barr virus and microsatellite instability subtypes and was an independent adverse prognostic factor in the GS subtype. In the TCGA subtypes, ARID1A negative expression caused increased CD4 and PD-L1 expression, whereas CD8 expression appeared independent of ARID1A. The expression of CD4/CD8 induced by ARID1A negativity was accompanied by an increase in PD-L1 expression.
富含 AT 相互作用结构域蛋白 1A（ARID1A）是 SWI/SNF 染色质重塑复合物的必需亚基，被认为是一种肿瘤抑制因子。癌症基因组图谱（TCGA）的分子分类在分子水平上加深了我们对胃癌的理解。本研究探讨了 ARID1A 在 TCGA 胃腺癌亚型中的表达意义。
我们收集了 1248 例胃腺癌术后患者，构建组织微阵列，进行 ARID1A 的免疫组织化学染色，并获得 ARID1A 与临床病理变量之间的相关性。然后，我们对 TCGA 亚型中的 ARID1A 进行预后分析。最后，我们通过随机抽样和倾向评分匹配方法筛选患者，并进行多重免疫荧光检测，以探讨 ARID1A 对 TCGA 亚型中 CD4、CD8 和 PD-L1 表达的影响。
筛选出与 ARID1A 相关的 7 个独立变量：错配修复蛋白、PD-L1、T 分期、分化状态、p53、E-钙黏蛋白和 EBER。在基因组稳定（GS）亚型中，独立的预后变量是 N 分期、M 分期、T 分期、化疗、肿瘤大小和 ARID1A。在所有 TCGA 亚组中，ARID1A 阴性组的 PD-L1 表达均高于 ARID1A 阳性组。在大多数亚型中，ARID1A 阴性组的 CD4 表达较高，而在大多数亚型中，CD8 表达没有差异。当 ARID1A 为阴性时，PD-L1 表达与 CD4/CD8 表达呈正相关；而当 ARID1A 为阳性时，这种相关性消失。
ARID1A 阴性表达在 EBV 和微卫星不稳定亚型中更为常见，是 GS 亚型中独立的不良预后因素。在 TCGA 亚型中，ARID1A 阴性表达导致 CD4 和 PD-L1 表达增加，而 CD8 表达与 ARID1A 无关。ARID1A 阴性表达诱导的 CD4/CD8 表达增加伴随着 PD-L1 表达的增加。
