The effect of BRCA1/2 mutation on breast cancer and its impact on PARP inhibitor treatments: Differential expression genes approach
Authors: Paramita Rafika Indah , Panigoro Sonar Soni , Wanandi Septelia Inawati , Fadilah Fadilah 
Published: June 2024

The occurrence of germline mutations within the BRCA1/2 genes has been linked to an elevated vulnerability toward the onset of breast cancer (BC). At present, ongoing clinical trials are being undertaken to evaluate the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors as a therapeutic intervention for BC, with particular emphasis on their application in the management of BC patients harboring BRCA1/2 gene mutations. The objective of this research was to investigate the presence of different expression genes in BC with BRCA1/2 mutations compared to the wild type and to evaluate the impact of PARP inhibitor therapy on the DEGs. This study utilized two distinct datasets sourced from the Gene Expression Omnibus (GEO) database. The initial datasets utilized in this study were GSE25835 and GSE40115. These datasets were employed to conduct a comparative analysis of differentially expressed genes (DEGs) in BC cases with BRCA1/2 mutations and those with wild-type status. Whereas in the GSE55399 dataset, the DEGs were compared between PARP inhibitor treatment and no PARP inhibitor treatment. The interactions among DEGs were assessed utilizing the search tool for the retrieval of interacting genes/proteins tool and subsequently displayed through the use of Cytoscape software. The molecular complex detection technique was employed for the identification of gene clusters within the interaction network. The DEGs that were discovered were further analyzed for gene ontology (GO) enrichment using Enrichr and CLueGO. Furthermore, the biological pathways linked to these DEGs were examined using REACTOME. We got significant DEGs by using parameter p-value of 0.05; log2FC > 1 and log2FC < −1. The GO analysis conducted on the DEGs revealed their significant involvement in crucial biological processes and molecular pathways. For datasets GSE25835 and GSE40115, it showed the effect on BRCA1/2 mutations was upregulating cell cycle response and downregulating mRNA splicing. For dataset GSE55399, the impact of PARP inhibitor treatments was upregulating the interferon signaling and downregulating the cytokine signaling. Our study identified hub genes of cell cycle response (CDK1 and BIRC5) that are strongly linked to BRCA1/2 mutation and hub genes of interferon signaling interferon-induced transmembrane 1 (IFITM1) and cytokine signaling (IL11) that are strongly linked to PARP inhibitor treatments in BRCA1/2 mutant carriers. We identified hub genes of cell cycle response (CDK1 and BIRC5) that are strongly linked to BRCA1/2 mutation. PARP inhibitor treatments in BRCA1/2 mutant carriers are strongly related to the upregulation of IFITM1 (interferon signaling) and the downregulation of IL11 (cytokine signaling). Therefore, PARP inhibitors may improve the treatment by activation/modulation the immune system and attenuating the inflammatory response. However, the dataset used to analyze the DEGs of PARP inhibitor treatments in BRCA1/2 mutant carriers still used BC cell lines, forthcoming research may be able to use clinical patients as the subjects. Moreover, functional studies are further needed to validate this finding.