Podocalyxin variants and risk of prostate cancer and tumor aggressiveness

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 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.

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

“…Furthermore, gene expression studies revealed a positive correlation between expression of PODXL and expression of ETS1, a regulator of angiogenesis, in human vascular endothelial cells (11). PODXL has also been implicated in more aggressive forms of prostate cancer (12). The PODXL gene maps to chromosome 7q32-q33 (13), a region that has been linked to aggressive forms of prostate cancer and that exhibits a high frequency of allelic imbalance in prostate tumors (14)(15)(16).…”

Genetic Susceptibility to Aggressive Prostate Cancer

“…For instance, Casey et al (45) followed-up reports of linkage and allelic imbalance at 7q32-33 (35,36) by sequencing the gene podocalyxin (PODXL), which is a downstream target of the WT1 tumor suppressor implicated in h-catenin signaling. Somasiri et al had previously reported a correlation between podocalyxin expression and aggressive breast cancer (46).…”

Control of cell adhesion and migration by podocalyxin. Implication of Rac1 and Cdc42

“…PODXL has also been found in vascular endothelium, lung, brain, multipotent hematopoietic precursors, megakaryocytes and platelets [4,14,15], as well as in several types of tumors in which the expression levels appear to correlate with the metastatic capacity [16,17,18]. However, unlike the role of PODXL in the renal homeostasis, almost nothing is known about its physiological role in extrarenal tissues.…”