Kyung Hee University at Gangdong, Gangdong-Gu, Seoul, South Korea
Gwan Hee Han , Hanbyoul Cho , Hee Yun , Jae-Hoon Kim
Background: Mutations in breast cancer susceptibility gene type 1 and type 2 (BRCA1 and BRCA2) put women at a higher risk of developing epithelial ovarian cancer (EOC). In individual carrying BRCA1 mutation has about 39-49% of the probability developing EOC in a lifetime. With BRCA2 mutations, the probability of developing EOC is about 11- 18 %. EOC patients with BRCA mutations shows an advanced histological grade compared to patients with BRCA wile type and respond better to platinum therapy, showing better survival. Patients with BRCA mutation shows better response to the platinum therapy, because in the absence of functional BRCA protein, cells fail to repair intra-strand crosslinks formed by DNA cross linking agents such as platinum drugs, leading to apoptotic cell death. However, despite the good response to platinum-based chemotherapy, EOC patients inevitably develop resistance to platinum drugs resulting in disease recurrent and is a major roadblock in a clinical management of cancer that carry BRCA mutation. Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing. Methods: RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients were analysed with various bioinformatic tools including Spatial Analysis of Functional Enrichment (SAFE) analysis, and the bioinformatic analysis result was verified with variuos ovarian cancer cell lines and public data. Results: Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients. The results of our study showed 308 total differentially expressed genes (DEGs) with 138 upregulated genes and 170 downregulated genes. By applying Spatial Analysis of Functional Enrichment (SAFE) analysis, we investigated that G2/M transition of mitotic cell cycle, MAPK cascade, double strand break repair via homologous recombination were the enriched pathways with upregulation of PABPC1, DCAF13, RAD21, PACSIN3 and downregulation of GCG11, HECW2, PSMA1. Their altered expression was verified in ovarian cancer cell lines and public database which showed the significant altered expression of PACSIN3 was observed in ovarian cancer cell lines suggesting as a potential biomarker for EOC treatment. Conclusions: Platinum resistance BRCA mutation EOC is an important issue to overcome the low survival rate for EOC patients. However, until now, there was relatively not much studies in discovring the biomarker or candidate gene of target therapy. Therefore, here we suggest the PACSIN3 as a new candidate gene for target therapy in platinum resistance BRCA mutation EOC.
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