背景:开关/蔗糖不可发酵(SWI/SNF)复合物是一种进化保守的染色质重塑复合物,在许多肿瘤中表现出功能障碍,尤其是未分化癌.癌症干细胞(CSC)一种特殊类型的具有干细胞样特性的未分化癌细胞,在肿瘤细胞增殖中起重要作用,入侵,和转移。在未分化胃癌中,SWI/SNF复合物与临床病理特征的关系,CSC表型,预后尚未完全了解。
方法:我们收集了21例未分化/去分化胃癌患者的队列。接下来,我们对SWI/SNF复合物的五个亚基(ARID1A,ARID1B,SMARCA2、SMARCA4和SMARCB1),和四种错配修复蛋白(MLH1,PMS2,MSH2和MSH6),以及其他标志物,如p53,PD-L1和癌症干细胞(CSC)标志物(SOX2,SALL4)。然后,我们调查了SWI/SNF复合物亚基与临床病理特征的相关性,并进行了预后分析.
结果:我们观察到SMARCA2丢失12例(57.14%),其次是ARID1A(5例,23.81%)和SMARCA4(3例,14.29%)。14例(66.67%)失去任何一个SWI/SNF复合物亚基,包括3例SMARCA2和ARID1A共同丢失,SMARCA2和SMARCA4共失3例。相关分析显示,CSC表型在SWI/SNF复合体缺陷组中出现频率更高(P=0.0158)。生存分析显示,SWI/WNF复合物缺乏,未分化状态,CSC表型,SMARCA2和SMARCA4的丢失导致生存率下降。单变量和多变量Cox回归分析筛选出与预后较差相关的三个独立因素:未分化状态,SWI/SNF复合物缺乏,淋巴结转移。
结论:SWI/SNF复合物缺乏更可能导致CSC表型和更差的生存,并且是未分化/去分化胃癌的独立预后因素。
BACKGROUND: The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood.
METHODS: We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B,
SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis.
RESULTS: We observed
SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with
SMARCA2 and ARID1A co-loss, and 3 cases with
SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of
SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis.
CONCLUSIONS: The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.