Identification and Characterization of Immunogene-Related Alternative Splicing Patterns and Tumor Microenvironment Infiltration Patterns in Breast Cancer

SIMPLE SUMMARY: Aberrant immunogene-related alternative splicing (IGAS) pattern plays a pivotal role in pathogenesis, progression, and tumor microenvironment. However, the IGAS pattern of post-transcriptional mechanisms in breast cancer remains limited. Here, we performed a systematic analysis of IGAS patterns in breast cancer to assess the association between aberrant IGAS events, prognosis signatures, AS regulatory network, immune cell infiltration level and its marker gene expression, sensitivity to immunotherapy and chemotherapy, and heterogeneity of IGAS clusters. Generally, we demonstrated the prognostic signatures for IGAS events and immune cells, which were valuable information for breast cancer patients in predicting survival and directing immunotherapy and chemotherapy. ABSTRACT: Alternative splicing (AS) plays a crucial role in tumor development and tumor microenvironment (TME) formation. However, our current knowledge about AS, especially immunogene-related alternative splicing (IGAS) patterns in cancers, remains limited. Herein, we identified and characterized post-transcriptional mechanisms of breast cancer based on IGAS, TME, prognosis, and immuno/chemotherapy. We screened the differentially spliced IGAS events and constructed the IGAS prognostic model (p-values < 0.001, AUC = 0.939), which could be used as an independent prognostic factor. Besides, the AS regulatory network suggested a complex cooperative or competitive relationship between splicing factors and IGAS events, which explained the diversity of splice isoforms. In addition, more than half of the immune cells displayed varying degrees of infiltration in the IGAS risk groups, and the prognostic characteristics of IGAS demonstrated a remarkable and consistent trend correlation with the infiltration levels of immune cell types. The IGAS risk groups showed substantial differences in the sensitivity of immunotherapy and chemotherapy. Finally, IGAS clusters defined by unsupervised cluster analysis had distinct prognostic patterns, suggesting an essential heterogeneity of IGAS events. Significant differences in immune infiltration and unique prognostic capacity of immune cells were also detected in each IGAS cluster. In conclusion, our comprehensive analysis remarkably enhanced the understanding of IGAS patterns and TME in breast cancer, which may help clarify the underlying mechanisms of IGAS in neoplasia and provide clues to molecular mechanisms of oncogenesis and progression.