Exclusion of the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy in HPCX1-linked families.
Several linkage studies provided evidence for the presence of the hereditary prostate cancer locus, HPCX1, at Xq27-q28. The strongest linkage peak of prostate cancer overlies a variable region of ~750 kb at Xq27 enriched by segmental duplications (SDs), suggesting that the predisposition to prostate cancer may be a genomic disorder caused by recombinational interaction between SDs. The large size of SDs and their sequence similarity make it difficult to examine this region for possible rearrangements using standard methods. To overcome this problem, direct isolation of a set of genomic segments by in vivo recombination in yeast (a TAR cloning technique) was used to perform a mutational analysis of the 750 kb region in X-linked families. We did not detect disease-specific rearrangements within this region. In addition, transcriptome and computational analyses were performed to search for nonannotated genes within the Xq27 region, which may be associated with genetic predisposition to prostate cancer. Two candidate genes were identified, one of which is a novel gene termed SPANXL that represents a highly diverged member of the SPANX gene family, and the previously described CDR1 gene that is expressed at a high level in both normal and malignant prostate cells, and mapped 210 kb of upstream the SPANX gene cluster. No disease-specific alterations were identified in these genes. Our results exclude the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy. Adjacent regions appear to be the most likely candidates to identify the elusive HPCX1 locus.
Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, MD, USA. kouprinn@mail.nih.gov
Natalay
N
Kouprina
Nicholas C O
NC
Lee
Adam
A
Pavlicek
Alexander
A
Samoshkin
Jung-Hyun
JH
Kim
Hee-Sheung
HS
Lee
Sudhir
S
Varma
William C
WC
Reinhold
John
J
Otstot
Greg
G
Solomon
Sean
S
Davis
Paul S
PS
Meltzer
Johanna
J
Schleutker
Vladimir
V
Larionov
D001324:Autoantigens / Q000235:genetics; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D056916:Segmental Duplications, Genomic
D001324:Autoantigens; C063762:CDR1 protein, human; D004273:DNA, Neoplasm; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins