title: Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27.
abstract: Genetic linkage studies indicate that germline variations in a gene or genes on chromosome Xq27-28 are implicated in prostate carcinogenesis. The linkage peak of prostate cancer overlies a region of approximately 750 kb containing five SPANX genes (SPANX-A1, -A2, -B, -C, and -D) encoding sperm proteins associated with the nucleus; their expression was also detected in a variety of cancers. SPANX genes are >95% identical and reside within large segmental duplications (SDs) with a high level of similarity, which confounds mutational analysis of this gene family by routine PCR methods. In this work, we applied transformation-associated recombination cloning (TAR) in yeast to characterize individual SPANX genes from prostate cancer patients showing linkage to Xq27-28 and unaffected controls. Analysis of genomic TAR clones revealed a dynamic nature of the replicated region of linkage. Both frequent gene deletion/duplication and homology-based sequence transfer events were identified within the region and were presumably caused by recombinational interactions between SDs harboring the SPANX genes. These interactions contribute to diversity of the SPANX coding regions in humans. We speculate that the predisposition to prostate cancer in X-linked families is an example of a genomic disease caused by a specific architecture of the SPANX gene cluster.
authors.affiliation: Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Natalay
authors.initials: N
authors.lastname: Kouprina
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Noskov
authors.forename: Greg
authors.initials: G
authors.lastname: Solomon
authors.forename: John
authors.initials: J
authors.lastname: Otstot
authors.forename: William
authors.initials: W
authors.lastname: Isaacs
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: Joanna
authors.initials: J
authors.lastname: Schleutker
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: Jerzy
authors.initials: J
authors.lastname: Jurka
authors.forename: Vladimir
authors.initials: V
authors.lastname: Larionov
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D003001:Cloning, Molecular; D040461:Gene Components; D020440:Gene Duplication; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D015003:Yeasts
chemical_list: D009687:Nuclear Proteins; C414403:SPANXA1 protein, human; C521014:SPANXA2 protein, human; C521016:SPANXD protein, human