Abstract 1780: The MAD1 1673 GA polymorphism alters the function of the mitotic splindle assembly checkpoint and is asociated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer.

Abstract

Abstract Introduction: MAD1, a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A SNP of Mad1 was found to affect the SAC function that could be involved in a bad response to therapeutic agents that alter the dynamics of microtubules. Objective: To investigate the relationship of the polymorphism Mad1 1673 GA (rs1801368) with the efficiency of the SAC and the generation of aneuploidies, and with the therapeutic response of patients with ovarian cancer. Methods: The polymorphism was evaluated in 144 healthy individuals and 91 patients. The mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazol and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients. Results: Allele frequencies in healthy individuals were G: 50, A: 50, while in the patients, they were G: 38%, A: 62% (p<0.05). The percentage of cells with mitotic arrest was higher in GG cells (p<0.05). The frequency of micronuclei and nondisjunction events increased in AA cells (p<0.05). Tumors from polymorphic patients had a higher percentage of aneuploid cells (p<0.05). The GG patients showed a higher biochemical response, optimal cytoreduction and sensitivity to the treatment. There were no differences in progression-free or overall survival between both groups. Conclusions: the polymorphism Mad1 1673 GA affects the SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer. Citation Format: Miguel Santibañez, Dolores Gallardo, Flavia Morales, Alejandro Lopez, Diddier Prada, Julia Mendoza, Clementina Castro, David Cantu de Leon, Luis F. Oñate, Delia Perez, Alejandro Mohar, Luis A. Herrera. The MAD1 1673 GA polymorphism alters the function of the mitotic splindle assembly checkpoint and is asociated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2013-1780