title: Genetic variation in the major mitotic checkpoint genes associated with chromosomal aberrations in healthy humans.
abstract: Non-specific chromosomal aberrations (CAs) are microscopically detected in about 1% of lymphocytes drawn from healthy persons. Causes of CAs in general population are not known but they may be related to risk of cancer. In view of the importance of the mitotic checkpoint machinery on maintaining chromosomal integrity we selected 9 variants in main checkpoint related genes (BUB1B, BUB3, MAD2L1, CENPF, ESPL1/separase, NEK2, PTTG1/securin, ZWILCH and ZWINT) for a genotyping study on samples from healthy individuals (N = 330 to 729) whose lymphocytes had an increased number of CAs compared to persons with a low number of CAs. Genetic variation in individual genes played a minor importance, consistent with the high conservation and selection pressure of the checkpoint system. However, gene pairs were significantly associated with CAs: PTTG1-ZWILCH and PTTG1-ZWINT. MAD2L1 and PTTG1 were the most common partners in any of the two-way interactions. The results suggest that interactions at the level of cohesin (PTTG1) and kinetochore function (ZWINT, ZWILCH and MAD2L1) contribute to the frequency of CAs, suggesting that gene variants at different checkpoint functions appeared to be required for the formation of CAs.
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden. Electronic address: a.foersti@dkfz.de.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Frank
authors.affiliation: Department of Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 83391 Bratislava, Slovakia.
authors.forename: Bozena
authors.initials: B
authors.lastname: Smolkova
authors.affiliation: Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia.
authors.forename: Alena
authors.initials: A
authors.lastname: Kazimirova
authors.affiliation: Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Barancokova
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14200 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 12800 Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Vymetalkova
authors.affiliation: Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 12800 Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Kroupa
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14200 Prague, Czech Republic; Human Genetics Foundation, Turin, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14200 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 12800 Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.affiliation: Department of Public Health, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Sklabinska 26, 03601 Martin, Slovakia.
authors.forename: Janka
authors.initials: J
authors.lastname: Buchancova
authors.affiliation: Health Effects Laboratory, Department of Environmental Chemistry, NILU-Norwegian Institute for Air Research, Instituttveien 18, 2007 Kjeller, Norway.
authors.forename: Maria
authors.initials: M
authors.lastname: Dusinska
authors.affiliation: Clinic of Occupational Medicine and Toxicology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava and University Hospital Martin, Kollarova 2, 03601 Martin, Slovakia.
authors.forename: Ludovit
authors.initials: L
authors.lastname: Musak
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14200 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 12800 Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D018816:Genes, cdc; D014644:Genetic Variation; D064368:Healthy Volunteers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008214:Lymphocytes / Q000737:chemistry* / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D064246:Mad2 Proteins / Q000235:genetics; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000235:genetics; D064249:Securin / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D064249:Securin; C413695:ZWINT protein, human; C000606356:Zwilch protein, human; C578002:pituitary tumor-transforming protein 1, human
keywords: Chromosomal integrity; Cytogenetics; DNA double-stranded break; Spindle checkpoint