title: Association of genetic variation in mitotic kinases with breast cancer risk.
abstract: An RNAi-based functional screening of mitotic kinases in Drosophila recently identified a number of members of the kinome that are required for normal cell division. Depletion of these kinases resulted in a number of different mitotic abnormalities including spindle malformation, chromosome mis-segregation, centrosome amplification and failure of cytokinesis (Bettencourt-Dias et al. in Nature 432:980-987, 2004). Since mitotic defects are commonly observed in cancer cells, these kinases may contribute to tumor development and/or progression. To investigate whether common genetic variation in the mitotic kinases are associated with breast cancer risk, we genotyped 386 single nucleotide polymorphisms (SNPs) from 44 mitotic kinase genes, in 798 breast cancer cases and 843 unaffected controls from a clinic-based study. A total of 22 SNPs from 13 kinase genes displayed significant associations with breast cancer risk (P(trend) < or = 0.05), including two SNPs from FYN (rs6914091 and rs1465061) that remained of interest after accounting for multiple testing (q = 0.06). These associations were stronger when evaluating cases with estrogen and progesterone receptor positive tumors. In addition, haplotype-based tests identified significant associations with risk for common haplotypes of the MAST2 (P = 0.04) and MAP2K4 (P = 0.006) genes. Although requiring replication, these findings suggest that genetic polymorphisms in mitotic kinases that have been implicated in chromosome instability and aneuploidy may contribute to the development of breast cancer.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. wangx1@mayo.edu
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Fredericksen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Kosel
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D015146:Midwestern United States / Q000453:epidemiology; D008938:Mitosis / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D011494:Protein Kinases