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Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27

¹ Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA ² Genetic Information Research Institute, Mountain View, California 94043, USA ³ Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA ⁴ Department of Urology, Johns Hopkins University, Baltimore, Maryland 21287, USA ⁵ Translational Genomics Research Institute, Phoenix, Texas 85004, USA ⁶ Laboratory of Cancer Genetics, Institute of Medical Technology, FIN-33014 University of Tampere, Finland

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 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.

Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.4212705. Freely available online through the Genome Research Immediate Open Access option.

⁷ Corresponding author.
E-mail larionov{at}mail.nih.gov; fax (301) 480-2772.

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