187P - BUB1 (2530C>T) polymorphism and expression affects chemotherapy response and predicts poor prognosis in advanced epithelial ovarian cancer

Background

Ovarian cancer (OC) is a frequent gynecological cancer with a complex pathophysiology and high mortality. This study determines roles of 2530C>T SNP in BUB1, a key component of spindle assembly checkpoint (SAC), and its expression in advanced OC pathology & treatment outcome.

Methods

77 advanced epithelial OC patients were recruited, who received postoperative adjuvant [I.V. doses of 175mg/m2 paclitaxel+ carboplatin AUC 5-6mg.min/mL] or neoadjuvant chemotherapy with interval debulking surgery. Their demographics, clinical parameters, toxicity and survival were recorded. BUB1(2530C>T) SNP was detected by the PCR-RFLP followed by sequencing. BUB1 expression, BUB1mRNA and miRNA-495 were assessed using IHC & qRT-PCR.

Results

Stages III (82·02%) and IV (17·98%) OC patients were mostly 41-60 (60%) years old. 37%, 40%, 23%% were categorized as responders (Rs), partial responders (PRs) and non-responders (NRs) with significantly different (p<0.05) survival outcomes. The polymorphic homozygous genotypes (CC) and (TT) of 2530C>T were most prevalent in NRs & PRs respectively showing significant association in chemotherapy response (p=0.021). The allele frequencies were found to be C= 0.2215, and T= 0.7784. The standard regimen was well tolerated but no significant relationship was observed between SNP and toxicities. The survival outcome was nearly significant (p= 0.06) showing association of CC genotype with higher risk (HR=9.938, 95%CI= 1.19-82.9) when compared to CT (HR=0.885, 95%CI= 0.109-7.19) and TT (HR=0.409, 95%CI= 0.049-2.209). 97.6% of biopsy samples showed low to moderate BUB1 IHC expression and did not have significant association with clinical response (p=0.32). BUB1 mRNA and miR-495 analysis revealed a Ct mean of 37.42 and 27.614 respectively. There was a negative correlation between BUB1mRNA and miR-495 levels (r= -0.551, p=0.16).

Conclusions

The homozygous polymorphic phenotypes of 2530C>T are significantly associated with chemotherapy response and poor survival outcomes but not related to chemo-induced toxicity. The very low expression of BUB1 may be attributed to regulation by miR-495. The negative expression also suggests a deficient SAC response in the advanced tumour.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vilas D Nasare.

Funding

Funded by Department of Health Research, Govt. of India under Young Scientist- Human Resources Development (HRD) Scheme (R.12014/12/2018-HR), received to Sarkar, S.

Disclosure

S. Sarkar: Non-Financial Interests, Institutional, Affiliate, Currently registered as a PhD Scholar at Department of Pharmaceutical Technology, Jadavpur University. All other authors have declared no conflicts of interest.