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Human Molecular Genetics Advance Access published online on January 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi487
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received October 13, 2005
Revised January 13, 2006
Accepted January 13, 2006

Article

Podocalyxin Variants and Risk of Prostate Cancer and Tumor Aggressiveness

Graham Casey 1 *, Phillippa J. Neville 2, Xin Liu 3, Sarah J. Plummer 2, Mine S. Cicek 2, Lisa M. Krumroy 2, Anthony P. Curran 2, Michelle R. McGreevy 2, William J. Catalona 4, Eric A. Klein 5, and John S. Witte 3

1 Department of Cancer Biology, ND50, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
2 Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195
3 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143
4 Department of Urologic Surgery, Northwestern University, Chicago, IL 60611
5 Glickman Urological Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195

* To whom correspondence should be addressed.
Graham Casey, E-mail: caseyg{at}ccf.org


  Abstract

We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the gene podocalyxin-like (PODXL), which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer (OR = 2.14, 95% CI = 1.09 - 4.20, p = 0.03), and the presence of two copies of any deletion further increased risk (OR = 2.58, 95% CI = 1.23 - 5.45, p = 0.01. This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR = 3.04 for one deletion (95% CI = 1.01 - 9.15), and OR = 4.42 for two deletions (95% CI = 1.32-14.85, p = 0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR = 1.48, 95% CI = 1.02 - 2.14, p = 0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.


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