Checkpoint Genes in Check: Impact of BUB1, BUB1B, and MAD2 Alterations on the Treatment Outcomes of Advanced Ovarian Cancer

Background: Spindle assembly checkpoint (SAC) prevents metaphase to anaphase transition during error-prone kinetochore attachments of the sister chromatids and is targeted by cytotoxic drugs like taxanes. BUB1, BUBR1, and MAD2 are key proteins involved in the activation of SAC to prevent inaccurate chromosome segregation. Objective: This study aims to analyze the associations of single nucleotide polymorphisms (BUB1B [rs28989186], MAD2L1 [rs1972014]) and expressions (BUB1 and MAD2) of SAC components with therapeutic outcome of paclitaxel and carboplatin for advanced ovarian cancer (OC) patients. In addition, miR-495 and miR-143 were analyzed to investigate their correlation with BUB1 and MAD2 expressions. Materials and Methods: Eighty advanced epithelial OC patients (FIGO Stages III and IV) were recruited who underwent treatment with paclitaxel–carboplatin chemotherapy (six cycles) and cytoreductive surgeries. Immunohistochemistry was performed for BUB1 and MAD2 expression analysis. qRT-PCR was done for mRNAs, miR-495, and mir-143 assessment from cancer tissues. Genetic polymorphisms were detected following DNA isolation from whole blood, using polymerase chain reaction-restriction fragment length polymorphism and sequencing. Results were statistically analyzed. Results: A total of 29, 32, and 19 were evaluated as responders, partial, and nonresponders, respectively, with significant survival outcomes ( P = 0.019). BUB1 was downregulated with miR-495 involvement, while MAD2 was upregulated in majority of advanced tumors with significant survival impact ( P = 0.001). BUB1B and MAD2L1 polymorphisms were significantly associated with chemotherapy-induced anemia, anxiety, diarrhea, constipation, and renal toxicity ( P < 0.05). Conclusion: Upregulation of MAD2 and downregulation of BUB1, with presence of rs1972014 and rs28989186, correlate with poor survival outcome and chemotherapy-induced adverse side effects in advanced OC.