title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors: Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, Universidad Nacional Autónoma de México, México, DF, México.
authors: Miguel
authors: M
authors: Santibáñez
authors: Dolores
authors: D
authors: Gallardo
authors: Flavia
authors: F
authors: Morales
authors: Alejandro
authors: A
authors: López
authors: Diddier
authors: D
authors: Prada
authors: Julia
authors: J
authors: Mendoza
authors: Clementina
authors: C
authors: Castro
authors: David Cantú
authors: DC
authors: de León
authors: Luis F
authors: LF
authors: Oñate
authors: Delia
authors: D
authors: Perez
authors: Alejandro
authors: A
authors: Mohar
authors: Luis A
authors: LA
authors: Herrera
mesh_terms: D054316:Biomarkers, Pharmacological; D002135:Calcium-Binding Proteins / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins / Q000235:genetics*; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D064246:Mad2 Proteins; D008870:Microtubules / Q000473:pathology; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D054316:Biomarkers, Pharmacological; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D017239:Paclitaxel; D015739:Nocodazole