Podocalyxin variants and risk of prostate cancer and tumor aggressiveness.
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 podocalyxin-like (PODXL) gene, 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 variants 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 [odds ratio (OR)=2.14, 95% confidence interval (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.
Casey
Graham
G
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. caseyg@ccf.org
Neville
Phillippa J
PJ
Liu
Xin
X
Plummer
Sarah J
SJ
Cicek
Mine S
MS
Krumroy
Lisa M
LM
Curran
Anthony P
AP
McGreevy
Michelle R
MR
Catalona
William J
WJ
Klein
Eric A
EA
Witte
John S
JS
D001741:Black or African American / Q000235:genetics; D022981:Allelic Imbalance; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D016001:Confidence Intervals; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D005091:Exons; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D021141:Nucleic Acid Amplification Techniques; D016017:Odds Ratio; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D012189:Retrospective Studies; D012306:Risk; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D012795:Sialoglycoproteins / Q000235:genetics*
D004273:DNA, Neoplasm; D005819:Genetic Markers; D012795:Sialoglycoproteins; C001643:podocalyxin; D017430:Prostate-Specific Antigen