Construction and Validation of a Newly Prognostic Signature for CRISPR-Cas9-Based Cancer Dependency Map Genes in Breast Cancer

Abstract

Cancer Dependency Map (CDM) genes comprise an extensive series of genome-scale RNAi-based loss-of-function tests; hence, it served as a method based on the CRISPR-Cas9 technique that could assist scientists in investigating potential gene functions. These CDM genes have a role in tumor cell survival and proliferation, suggesting that they may be used as new therapeutic targets for some malignant tumors. So far, there have been less research on the involvement of CDM genes in breast cancer, and only a tiny percentage of CDM genes have been studied. In this study, information of patients with breast cancer was extracted from The Cancer Genome Atlas (TCGA), from which differentially expressed CDM genes in breast cancer were determined. A variety of bioinformatics techniques were used to assess the functions and prognostic relevance of these confirmed CDM genes. In all, 290 CDM genes were found differentially expressed. Six CDM genes (SRF, RAD51, PMF1, EXOSC3, EXOC1, and TSEN54) were found to be associated with the prognosis of breast cancer samples. Based on the expression of the identified CDM genes and their coefficients, a prognosis model was constructed for prediction, according to which patients with breast cancer were separated into two risk groups. Those with high risk had substantially poorer overall survival (OS) than patients in the other risk group in the TCGA training set, TCGA testing set, and an external cohort from Gene Expression Omnibus (GEO) database. The area under the receiver operating characteristic (ROC) curve for this prognostic signature was, respectively, 0.717 and 0.635 for TCGA training and testing sets, demonstrating its reliability in predicting the prognosis of patients with breast cancer. We next created a nomogram using the six CDM genes discovered to create a therapeutically useful model. The Human Protein Atlas database was used to acquire all immunohistochemistry staining images of the discovered CDM genes. The proportions of tumor-infiltrating immune cells, as well as the expression levels of checkpoint genes, varied substantially between the two risk groups, according to the analyses of immune response. In conclusion, the findings of this research may aid in the understanding of the prognostic value and biological roles of CDM genes in breast cancer.