Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Sci. 2020 Mar;111(3):1008-1019. doi: 10.1111/cas.14301. Epub 2020 Jan 28.
ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.
ARID1A 是 SWI/SNF 染色质重塑复合物的亚基之一，在具有微卫星不稳定（MSI）的胃癌中经常发生突变。已经报道了实体型低分化腺癌（PDA）中最常见的 MSI，但实体型 PDA 中的 SWI/SNF 复合物状态在很大程度上仍然未知。我们回顾性分析了 54 例实体型 PDA 中错配修复（MMR）蛋白（MLH1、PMS2、MSH2 和 MSH6）、SWI/SNF 复合物亚基（ARID1A、INI1、BRG1、BRM、BAF155 和 BAF170）和 EBER 的表达，以及 KRAS 和 BRAF 的突变。我们分析了 40 例另一种组织学类型的胃癌作为对照组。实体型 PDAs 显示共存的腺体成分（76%）、MMR 缺陷（39%）以及 ARID1A 完全/部分缺失（31%/7%）、INI1（4%/4%）、BRG1（48%/30%）、BRM（33%/33%）、BAF155（13%/41%）和 BAF170（6%/2%）、EBER 阳性（4%）、KRAS 突变（2%）和 BRAF 突变（2%）。与对照组相比，MMR 缺陷以及 ARID1A、BRG1、BRM 和 BAF155 的缺失在实体型 PDAs 中明显更为频繁。MMR 缺陷与 ARID1A、BRG1 和 BAF155 在实体型 PDAs 中的缺失相关。在 MMR 缺陷组中，与腺体成分相比，实体成分中 ARID1A、BRG1、BRM 和 BAF155 的缺失明显更为频繁（P =.0268，P =.0181，P =.0224 和 P =.0071）。在 MMR 功能正常组中，与腺体成分相比，实体成分中 BRG1 的缺失明显更为频繁（P =.012）。总之，实体型 PDAs 显示 MMR 蛋白和 SWI/SNF 复合物的频繁缺失。我们认为 SWI/SNF 复合物的缺失可能会导致分化型腺癌向实体型 PDA 的形态转变。
