Genotyping and functional analysis of the D104N variant of human endostatin.
Endostatin is an endogenous inhibitor of angiogenesis derived from the extracellular matrix protein collagen XVIII. It has been reported that a variation at the 104 position (D104N) of human endostatin is associated with an increased risk of prostate cancer, potentially indicating that this protein variant is less active as an anti-angiogenic agent. Herein we reported the results of genotyping 389 patients with androgen independent prostate cancer (AIPC) and 352 normal control individuals for D104N endostatin. There was no significant association between the frequency of 104N endostatin and the incidence of AIPC in either Caucasian or African American patients compared to controls (15% Caucasian AIPC versus 13.7% in Caucasian controls, p=0.79; 7.4% African American AIPC versus 5.6% in African American controls, p=0.64). Actuarial analysis revealed no statistically significant association between incidence of the DN heterozygous genotype and survival (p=0.62 by logrank test). To study the functional significance of the D104N conversion, we have expressed and purified insoluble recombinant human 104D and 104N endostatin and compared their respective activities in human umbilical vein endothelial cell (HUVEC) tube formation assays. The 104N variant of human endostatin inhibited HUVEC tube formation at least as well as the wild-type form. We concluded that the D104N variation in human endostatin is neither clinically relevant nor suitable as a pharmacogenomic endpoint to assess the risk for developing AIPC.
Macpherson
Gordon R
GR
Molecular Pharmacology Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
Singh
Arun S
AS
Bennett
Charles L
CL
Venzon
David J
DJ
Liewehr
David J
DJ
Franks
Michael E
ME
Dahut
William L
WL
Kantoff
Philip W
PW
Price
Douglas K
DK
Figg
William D
WD
D000368:Aged; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D043169:Endostatins / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005799:Genes, Dominant; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism / Q000473:pathology
D020533:Angiogenesis Inhibitors; D043169:Endostatins