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

• Published in: Genome research Vol. 15; no. 11; pp. 1477 - 1486
• Main Authors: Kouprina, Natalay, Pavlicek, Adam, Noskov, Vladimir N, Solomon, Greg, Otstot, John, Isaacs, William, Carpten, John D, Trent, Jeffrey M, Schleutker, Joanna, Barrett, J Carl, Jurka, Jerzy, Larionov, Vladimir
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-11-2005
• Subjects: Base Sequence; Chromosome Mapping; Chromosomes, Human, X - genetics; Cloning, Molecular; Gene Components; Gene Duplication; Genetic Linkage - genetics; Genetic Predisposition to Disease; Genomics - methods; Humans; Male; Molecular Sequence Data; Nuclear Proteins - genetics; Prostatic Neoplasms - genetics; Recombination, Genetic - genetics; Sequence Analysis, DNA; Yeasts
• ISSN: 1088-9051; 1549-5469
• DOI: 10.1101/gr.4212705

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.