The MAD1 1673 G→A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer

BACKGROUNDMitotic arrest deficient 1 (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 single nucleotide polymorphism of MAD1 was found to affect the SAC function that could be involved in a poor response to therapeutic agents that alter the dynamics of microtubules. OBJECTIVEThe aim of this study was to examine the relationship of the polymorphism MAD1 1673 G→A (rs1801368) with the efficiency of the SAC and the generation of aneuploidies and with the therapeutic response of patients with ovarian cancer. METHODSThe polymorphism was evaluated in 144 healthy individuals and 91 patients. Mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazole and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients. RESULTSAllele frequencies in healthy individuals were G50%, A50%, whereas in the patients they were G38%, A62% (P