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

Miguel Santibáñez, Dolores Gallardo, Flavia Morales, Alejandro López, Diddier Prada, Julia Mendoza, Clementina Castro, David Cantú De León, Luis F. Oñate, Delia Perez, Alejandro Mohar, Luis A. Herrera

    Research output: Contribution to journalArticlepeer-review

    10 Scopus citations

    Abstract

    BACKGROUND: Mitotic 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. OBJECTIVE: The 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. METHODS: The 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. RESULTS: Allele frequencies in healthy individuals were G: 50%, A: 50%, whereas in the patients they were G: 38%, A: 62% (P<0.05). The percentage of cells with mitotic arrest was higher among 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. CONCLUSION: The polymorphism MAD1 1673 G→A affects 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.

    Original languageEnglish (US)
    Pages (from-to)190-199
    Number of pages10
    JournalPharmacogenetics and Genomics
    Volume23
    Issue number4
    DOIs
    StatePublished - Apr 2013

    Keywords

    • aneuploidy
    • chromosomal instability
    • gynecological cancer
    • nondisjunction
    • ovary
    • treatment response

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Genetics
    • Pharmacology, Toxicology and Pharmaceutics(all)
    • Genetics(clinical)

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