Immune checkpoint blockade (ICB) has been a major breakthrough in various cancers including gastric cancer (GC), yet the clinical outcomes remain poor. Currently, epithelial-mesenchymal transition (EMT) has been reported to be associated with tumor mutational burden (TMB), which can cause lack of response to ICB. However, the underlying mechanism remains unknown. Members of the transforming growth factorβ (TGFB) family are regarded as the main mediators of EMT, yet how TGFB2 drives EMT in GC is not fully understood. In this study, we found that overexpression of TGFB2 was correlated with poor prognosis in TGCA-STAD and four GEO GC datasets.Gene set enrichment analysis revealed that the EMT pathway was significantly enriched in the high TGFB2 expression group, whilst the TMB-related pathways including mismatch repair, base excision repair, and DNA replication were strongly enriched in the low expression group. Furthermore, EMT score analysis, WGCNA and functional analysis showed that TGFB2 was co-expressed with neurite-related pathways that might drive EMT. Also, CIBERSORT analysis revealed that tumor-infiltrating immune cells like T follicular helper cells might participate in the process of TGFB2 affecting TMB levels in GC. Moreover, in other various cancers, TGFB2 was also negatively correlated with TMB levels as well as ICB response. Overall, these results revealed that TGFB2 could play a vital role in linking EMT and TMB in GC, suggesting that TGFB2 may be a predictive therapeutic target for GC.
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http://dx.doi.org/10.1016/j.intimp.2020.106532 | DOI Listing |
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