Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer.
BACKGROUND
Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.


METHODS
We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.


RESULTS
After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10(-4)); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R(2) = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.


CONCLUSIONS
Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.


CONCLUSIONS
Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.
Gu
Fangyi
F
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Schumacher
Fredrick R
FR
Canzian
Federico
F
Allen
Naomi E
NE
Albanes
Demetrius
D
Berg
Christine D
CD
Berndt
Sonja I
SI
Boeing
Heiner
H
Bueno-de-Mesquita
H Bas
HB
Buring
Julie E
JE
Chabbert-Buffet
Nathalie
N
Chanock
Stephen J
SJ
Clavel-Chapelon
Françoise
F
Dumeaux
Vanessa
V
Gaziano
J Michael
JM
Giovannucci
Edward L
EL
Haiman
Christopher A
CA
Hankinson
Susan E
SE
Hayes
Richard B
RB
Henderson
Brian E
BE
Hunter
David J
DJ
Hoover
Robert N
RN
Johansson
Mattias
M
Key
Timothy J
TJ
Khaw
Kay-Tee
KT
Kolonel
Laurence N
LN
Lagiou
Pagona
P
Lee
I-Min
IM
LeMarchand
Loic
L
Lund
Eiliv
E
Ma
Jing
J
Onland-Moret
N Charlotte
NC
Overvad
Kim
K
Rodriguez
Laudina
L
Sacerdote
Carlotta
C
Sánchez
Maria-José
MJ
Stampfer
Meir J
MJ
Stattin
Pär
P
Stram
Daniel O
DO
Thomas
Gilles
G
Thun
Michael J
MJ
Tjønneland
Anne
A
Trichopoulos
Dimitrios
D
Tumino
Rosario
R
Virtamo
Jarmo
J
Weinstein
Stephanie J
SJ
Willett
Walter C
WC
Yeager
Meredith
M
Zhang
Shumin M
SM
Kaaks
Rudolf
R
Riboli
Elio
E
Ziegler
Regina G
RG
Kraft
Peter
P
D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics*; D017481:Receptors, Somatostatin / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D017481:Receptors, Somatostatin; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I; C094573:somatostatin receptor 5
Int J Cancer. 2003 Oct 20;107(1):60-4
12925957
Nat Rev Cancer. 2005 Dec;5(12):977-85
16341085
Am J Hum Genet. 2008 Oct;83(4):535-9; author reply 539-40
18940314
Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2461-6
17164371
J Natl Cancer Inst. 2002 Jul 17;94(14):1099-106
12122101
Lancet Oncol. 2010 Jun;11(6):530-42
20472501
Int J Cancer. 2007 Nov 15;121(10):2267-73
17597108
Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):699-704
15767352
Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1319-21
15894694
J Clin Endocrinol Metab. 2007 Sep;92(9):3660-6
17566087
Acta Endocrinol (Copenh). 1989 Dec;121(6):753-8
2558477
Endocr Relat Cancer. 2006 Jun;13(2):273-8
16728563
PLoS One. 2008 Jul 02;3(7):e2578
18596909
Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):573-82
15066922
Stat Med. 2002 Jun 15;21(11):1539-58
12111919
Br J Cancer. 2006 Jan 30;94(2):299-307
16404426
Hum Mol Genet. 2010 Oct 1;19(19):3873-84
20634197
J Biol Chem. 1989 Jul 15;264(20):11843-8
2473065
J Biol Chem. 1998 Mar 13;273(11):6074-9
9497324
Cancer Epidemiol Biomarkers Prev. 2003 Feb;12(2):84-9
12582016
J Clin Endocrinol Metab. 1994 Feb;78(2):310-2
8106617
Cancer Epidemiol Biomarkers Prev. 2004 Aug;13(8):1290-5
15298948
J Clin Invest. 1996 Dec 1;98(11):2612-5
8958225
Control Clin Trials. 2000 Dec;21(6 Suppl):349S-355S
11189687
Science. 2002 Jun 21;296(5576):2225-9
12029063
Cancer Epidemiol Biomarkers Prev. 2001 Apr;10(4):377-84
11319179
Cancer Causes Control. 2005 Apr;16(3):255-62
15947877
Genet Epidemiol. 2008 May;32(4):361-9
18271029
J Clin Endocrinol Metab. 2007 Dec;92(12):4820-6
17911177
Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):2-19
15668470
J Clin Endocrinol Metab. 2005 Aug;90(8):4824-8
15914528
Hum Mol Genet. 2010 Aug 1;19(15):3089-101
20484221
Br J Cancer. 2003 Jan 27;88(2):277-82
12610514
Endocr Rev. 1994 Feb;15(1):80-101
8156941
Breast Cancer Res. 2007;9(1):R18
17300730
Stat Med. 2008 Feb 28;27(5):625-50
17590884
J Clin Endocrinol Metab. 2001 Mar;86(3):1274-80
11238520
Cancer Res. 2003 Jul 15;63(14):3991-4
12873996
Public Health Nutr. 2002 Dec;5(6B):1113-24
12639222
J Clin Endocrinol Metab. 1990 May;70(5):1347-53
1692332
Int J Cancer. 2009 May 15;124(10):2416-29
19142965
Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2316-25
16214911
Hum Hered. 2003;55(1):27-36
12890923
Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1644-50
19423539
J Endocrinol Invest. 1999;22(5 Suppl):48-57
10442571
Nat Genet. 2005 Nov;37(11):1217-23
16244653
Nat Rev Cancer. 2005 May;5(5):388-96
15864280
Nat Rev Cancer. 2004 Jul;4(7):505-18
15229476
Am J Epidemiol. 2000 Feb 15;151(4):346-57
10695593
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D528-32
14681474
Ann Intern Med. 2008 Oct 7;149(7):461-71, W83-8
18838726
Hum Mol Genet. 2006 Jan 1;15(1):1-10
16306136
J Clin Endocrinol Metab. 2003 Nov;88(11):5353-60
14602773
Ann Epidemiol. 1994 Jan;4(1):1-10
8205268