Polymorphism in endostatin, an angiogenesis inhibitor, and prostate cancer risk and survival: A prospective study.
Endostatin inhibits endothelial cell proliferation and migration, prerequisites of angiogenesis. A functional missense mutation (D104N) in endostatin was associated with an increased prostate cancer risk in a small study. We undertook a larger, prospective study within the Physicians' Health Study to examine D104N and prostate cancer risk and progression among 544 incident prostate cancer cases (1982-1995) and 678 matched controls. The association between endostatin genotype and cancer risk was estimated using logistic regression models. Among cases, Cox models were used to assess D104N and lethal prostate cancer. Given the role of endostatin in neovascularization of adipose tissue, we cross classified individuals on D104N genotype and body mass index (BMI). The genotype frequency was 1.3% homozygous (NN), 14.5% heterozygous (DN) and 84.2% wildtype homozygous (DD). There was no overall association between carriage of the N allele and prostate cancer risk (RR = 1.2, 95% CI: 0.9-1.6) or cancer-specific mortality (HR = 1.2, 0.7-1.8). Cases with the polymorphic allele were less likely to be overweight (BMI 25 kg/m(2) or greater, 26%) compared to men wildtype homozygous (48%), p < 0.0001. Being overweight was associated with a 60% greater prostate cancer risk among those who were wildtype homozygous. In contrast, being overweight was associated with a 50% lower risk of cancer among those with the N allele. We did not confirm an earlier observation between the D104N polymorphism and prostate cancer. However, our data indicate that prostate cancer cases who carry the variant N allele are more likely to be overweight, and may be more susceptible to the angiogenic influences of obesity in prostate cancer pathogenesis.
Mucci
Lorelei A
LA
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. lmucci@hsph.harvard.edu
Stark
Jennifer R
JR
Figg
William D
WD
Schumacher
Fredrick
F
Li
Haojie
H
Abe
Miyako
M
Hennessy
Kristen
K
Stampfer
Meir J
MJ
Gaziano
John Michael
JM
Ma
Jing
J
Kantoff
Philip W
PW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000235:genetics*; D015992:Body Mass Index; D016022:Case-Control Studies; D043169:Endostatins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000401:mortality / Q000473:pathology; D050177:Overweight / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D015996:Survival Rate
D020533:Angiogenesis Inhibitors; D043169:Endostatins