The relationship of polymorphism Mad1 1673 G>A on outcomes in patients with advanced ovarian cancer treated with carboplatine-paclitaxel.

Abstract

5050 Background: Genome integrity depends on the accurate segregation of chromosomes in mitosis. To maintain this condition, the spindle assembly checkpoint (SAC) activates a wait signal until all chromosomes are aligned in the metaphase plate. This arrest depends on the recruitment of a MAD1-MAD2 tetramer. The Mad1 1673 G>A polymorphism may disrupt the MAD1-MAD2 interaction. Results from our laboratory found a high frequency of this polymorphism in healthy individuals (HI). Here we analyzed the effect of this polymorphism in the mitotic arrest (MA) mediated by nocodazole (NDZ), and its influence in aneuploidy induction. Since a dysfunctional SAC could modify the clinical response to microtubule-disrupting drugs (i.e. paclitaxel, PTX), we also investigated the relationship of this polymorphism with disease progression, and survival in patients with advanced ovarian cancer (OCP) treated with carboplatine (CBP)-PTX. Methods: The polymorphism was evaluated by RFLP in lymphocytes from 144 HI. MA and aneuploidy induction were analyzed in cultured lymphocytes treated with 663 nM NDZ. The polymorphism was determined in blood and tumor samples from 73 OCP who received 3 cycles of 175 mg/m2 PTX and AUC6 CBP. Results: Allele distribution in HI was G: 50%, A: 50%, while in OCP was G: 38%, A: 62% (p<0.05). The percentage of cells in MA was 34% in AA and 71% in GG HI (p<0.05). Non-disjunction was increased in AA cells (p<0.05). Similarly, tumors from polymorphic OCP had a higher frequency of aneuploid cells (71% vs. 38% in GG OCP, p<0.05). There was a significant difference in progression free survival (PFS) between GG- and AA-OCP (HR 3.7; 95% CI, 1.1- 12.8; p= 0.026). Median PFS was 20 (GA) and 27 (AA) months shorter in polymorphic OCP compared to GG OCP. All GG OCP are alive at the present time compared with only 40% of polymorphic OCP (p=0.71). Conclusions: Our results show that the Mad1 1673 G>A polymorphism affects the functionality of the SAC, increasing the frequency of aneuploidy events in normal and tumor cells, and also modifies the response to microtubule-disrupting drugs hereby affecting the PFS and overall survival in OC patients.