Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.
BACKGROUND
The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.


METHODS
Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.


RESULTS
The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.


CONCLUSIONS
The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
Yin
Y
Cao
Sara
S
Lindström
Fredrick
F
Schumacher
Victoria L
VL
Stevens
Demetrius
D
Albanes
Sonja
S
Berndt
Heiner
H
Boeing
H Bas
HB
Bueno-de-Mesquita
Federico
F
Canzian
Saioa
S
Chamosa
Stephen J
SJ
Chanock
W Ryan
WR
Diver
Susan M
SM
Gapstur
J Michael
JM
Gaziano
Edward L
EL
Giovannucci
Christopher A
CA
Haiman
Brian
B
Henderson
Mattias
M
Johansson
Loïc
L
Le Marchand
Domenico
D
Palli
Bernard
B
Rosner
Afshan
A
Siddiq
Meir
M
Stampfer
Daniel O
DO
Stram
Rulla
R
Tamimi
Ruth C
RC
Travis
Dimitrios
D
Trichopoulos
Walter C
WC
Willett
Meredith
M
Yeager
Peter
P
Kraft
Ann W
AW
Hsing
Michael
M
Pollak
Xihong
X
Lin
Jing
J
Ma
D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000401:mortality*; D011506:Proteins / Q000235:genetics*; D017481:Receptors, Somatostatin / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D014408:Biomarkers, Tumor; C408145:IGF2-AS lncRNA, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D011506:Proteins; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; D007334:Insulin-Like Growth Factor I