Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.
The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade >or=8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling.
Koutros
Stella
S
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA. KoutrosS@mail.nih.gov
Schumacher
Fredrick R
FR
Hayes
Richard B
RB
Ma
Jing
J
Huang
Wen-Yi
WY
Albanes
Demetrius
D
Canzian
Federico
F
Chanock
Stephen J
SJ
Crawford
E David
ED
Diver
W Ryan
WR
Feigelson
Heather Spencer
HS
Giovanucci
Edward
E
Haiman
Christopher A
CA
Henderson
Brian E
BE
Hunter
David J
DJ
Kaaks
Rudolf
R
Kolonel
Laurence N
LN
Kraft
Peter
P
Le Marchand
Loïc
L
Riboli
Elio
E
Siddiq
Afshan
A
Stampfer
Mier J
MJ
Stram
Daniel O
DO
Thomas
Gilles
G
Travis
Ruth C
RC
Thun
Michael J
MJ
Yeager
Meredith
M
Berndt
Sonja I
SI
D000368:Aged; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology* / Q000235:genetics*
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases