Abstract
The clinicopathological significance of altered SWI/SNF complex has not been well evaluated in gastric cancer (GC). We examined SMARCA2, SMARCA4, SMARCB1 and ARID1A expression by immunohistochemistry in 1224 surgically resected GCs with subtyping into Epstein-Barr virus (EBV), microsatellite instability (MSI) and non-EBV/MSI Lauren histotypes. SWI/SNF mutations were investigated using the GC dataset of the TCGA Pan-Cancer Atlas. Clinicopathological association was assessed by statistical analysis. There were 427 cases (35%) of SWI/SNF-attenuated GC, including 344 SMARCA2 (28%), 28 SMARCA4 (2%), 11 SMARCB1 (1%) and 197 ARID1A (16%) cases. Simultaneous alterations of multiple subunits were observed. Compared to SWI/SNF-retained cases, SWI/SNF-attenuated GC exhibited a significant predilection to older ages, EBV and MSI genotypes, higher lymphatic invasion and less hematogenous recurrence (P < 0.05). SWI/SNF attenuation was an independent risk factor for short overall survival (P = 0.001, hazard ratio 1.360, 95% confidence interval 1.138-1.625). The survival impact stemmed from SMARCA2-attenuated GCs in stage III and non-EBV/MSI diffuse/mixed subtypes (P = 0.019 and < 0.001, respectively). ARID1A-lost/heterogeneous GCs were more aggressive in the EBV genotype (P = 0.016). SMARCB1 or SMARCA4 loss was not restricted to rhabdoid/undifferentiated carcinoma. In the TCGA dataset, 223 of 434 GCs (52%) harbored deleterious SWI/SNF mutations, including ARID1A (27%), SMARCA2 (9%), ARID2 (9%), ARID1B (8%), PBRM1 (7%), and SMARCA4 (7%). SWI/SNF-mutated GCs displayed a favorable outcome owing to the high percentage with the MSI genotype. In conclusion, SWI/SNF-altered GCs are common and the clinicopathological significance is related to the genotype.
Highlights
Gastric cancer (GC) continues to be ranked third in cancer-related mortality worldwide [1]
Compared to the Switch/ sucrose non-fermentable complex (SWI/SNF)-retained group, SWI/SNF-attenuated GCs showed a significant predisposition to older patients (Age > 65 years, 56% versus 49%, P = 0.021), Epstein-Barr virus (EBV) and microsatellite instability (MSI) genotypes (10% and 15% versus 3% and 7%, P < 0.001), patients with lymphatic invasion (63% versus 54%, P = 0.003) and patients without hematogenous recurrence (Table 1)
These 3 patterns are all regarded as SWI/SNF-attenuated GC based on previous observations that the SWI/SNF-lost phenomenon is caused by molecular alterations in the corresponding SWI/SNF subunits per se, and the SWI/SNF-reduced pattern is linked to secondary diminishment from alterations in other SWI/SNF subunits [7, 21]
Summary
Gastric cancer (GC) continues to be ranked third in cancer-related mortality worldwide [1]. Molecular knowledge regarding gastric carcinogenesis progresses dramatically. The Cancer Genome Atlas (TCGA) network used whole genome approaches to divide GC into Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI)-high, genomically stable (GS) and chromosomal instability (CIN) subtypes [2]. We integrated EBV-encoded small RNA in situ hybridization (EBER-ISH), immunohistochemistry of DNA mismatch repair proteins (MMR-IHC) and Lauren histotyping to design a practical GC subtyping algorithm, parallel to the TCGA classification [3]. The Lauren intestinal and diffuse/mixed division was done after EBV and MSI-associated GCs were subtracted. The nonEBV/MSI intestinal and diffuse/mixed subtypes had clinical and molecular similarity to the TCGA CIN and GS variants, respectively [3]
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