Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival.
BACKGROUND
Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival.


METHODS
Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register.


RESULTS
We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02).


CONCLUSIONS
Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.
Johansson
Mattias
M
International Agency for Research against Cancer, Lyon, France. johanssonm@fellows.iarc.fr
McKay
James D
JD
Rinaldi
Sabina
S
Wiklund
Fredrik
F
Adami
Hans-Olov
HO
Grönberg
Henrik
H
Kaaks
Rudolf
R
Stattin
Pär
P
D004273:DNA, Neoplasm / Q000032:analysis; D005838:Genotype; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood* / Q000235:genetics*; D008297:Male; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality*; D015996:Survival Rate; D013548:Sweden / Q000453:epidemiology
D004273:DNA, Neoplasm; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins