title: Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.
abstract: 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA. KoutrosS@mail.nih.gov
authors.forename: Stella
authors.initials: S
authors.lastname: Koutros
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Huang
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.forename: Heather Spencer
authors.initials: HS
authors.lastname: Feigelson
authors.forename: Edward
authors.initials: E
authors.lastname: Giovanucci
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.forename: Mier J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
mesh_terms: 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*
chemical_list: 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