Background:

The main component of this investigation is based in the ProtecT prostate cancer trial, co-ordinated from the School of Social and Community Medicine. This study is funded by a World Cancer Research Fund grant. We are applying to use ALSPAC data in order to conduct a validation exercise, and to perform a genome-wide association study (GWAS).

The nutritionally-regulated insulin-like growth factor (IGF) system, which includes two IGFs (IGF-I and IGF-II) and six IGF-binding proteins (IGFBP-1 to -6) play a key role in somatic growth, and activate potentially carcinogenic intracellular signalling networks. Many epidemiological studies observe positive associations of circulating IGF-I with prostate cancer but our recent systematic review highlights inconsistencies,[1] and it is unclear whether elevated IGF-I causes prostate cancer or reflects confounding or reverse causality. We have completed the largest single study we are aware of to investigate IGFs/IGFBPs in prostate cancer (ProtecT study), revealing strong positive associations of IGF-II, IGFBP-2 and IGFBP-3 with screen-detected prostate cancer (all p trendless than 0.001) but no association of serum IGF-I.[2] Our findings are consistent with other much smaller investigations for IGF-II, IGFBP-2 and IGFBP-3, but causality remains to be established.

Recently discovered genetic associations with prostate cancer are linked to the IGF-signalling pathway. In a genome-wide association study (GWAS),[3] 4 of 7 genotypes linked to prostate cancer are also involved in the IGF system: homozygous variants at insulin-IGF2 and NKX3.1 (an androgen-regulated tumour suppressor gene that regulates IGFBP-3) had up to a 50% increased prostate cancer risk, while homozygous variants at ITGA6 (encodes integrins that interact with IGFBPs) and PDLIM5 (inter-connected to an IGF-1R signaling protein that regulates migration) had up to a 65% decreased risk. Other common IGF-related genes (e.g. IGF-1R; PI3K; INS; IRS-1/-2) are associated with prostate or other cancers.[4-9]

Some genotypes are, simultaneously, related to both IGF/IGFBP levels and cancer; e.g. men homozygous for IGFBP-3 -202A/C promoter variants have lower circulating IGFBP-3,[10] a 2.5-fold increased prostate cancer risk[11] and a four-fold increased risk of metastatic disease.[12] IGF-1-variants are associated with both circulating IGF-I[8] and prostate (OR=1.46) [8] and breast (OR=1.4) [13] cancer; IGFBP-3 rs2270628 is associated with IGF-I and ovarian cancer (ORs=1.18-1.36).[14] There are very few studies relating genetic variants to IGF-II or IGFBP-2 levels. One GWAS relating genetic loci to circulating IGF-I and IGFBP-3 has been carried out in middle-aged adults, and identified several loci that were associated with IGFBP-3 and IGF-I concentrations.[15].

Aims:

We aim to clarify the role of the IGF system in prostate cancer, by using genetic variants as 'instruments' for measured circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 and conducting formal Mendelian randomization (MR) instrumental variables (IV) analyses to obtain causal (unconfounded and unbiased) odds ratios for associations of circulating IGFs/IGFBPs with prostate cancer initiation and progression. Application of MR will identify IGFs/IGFBPs that are causally important in prostate cancer initiation or progression, which could be manipulated for primary or secondary prostate cancer prevention. Some trials of dietary interventions to reduce IGFs/IGFBPs in men at high risk of cancer are already underway, but should only be warranted if a causal link is demonstrated, particularly given potential unintended IGF-related effects (e.g. on insulin resistance, cardiovascular disease and cognitive decline). If we determine, instead, that raised IGFs/IGFBPs are a consequence of prostate cancer (reverse causality), the focus of future research would shift to assessing these ligands as nutritionally-related biomarkers of diagnosis or cancer monitoring/surveillance.

Objectives:

1) To obtain unbiased estimates of the diection and magnitude of the the causal associations of circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 with prostate cancer prevalence, stage and grade, and disease progression. This will involve i) deriving genetic allele scores based on single nucleotide polymorphisms (SNPs) associated with IGF/IGFBP levels, in approximately 1000 controls from the ProtecT prostate cancer cohort; ii) validating the allele scores in ASLPAC children (or deriving new allele scores if we observe differences in SNP-IGF associations in adults versus children).

2) To conduct a genome-wide association study to identify SNPs associated with circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 during childhood, among children in ALSPAC.

Hypothesis:

Raised levels of circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 are causally associated with increased risk of prostate cancer overall; advanced stage and grade; and with disease progression.

Exposure:

GWAS (which will include selected variants in IGF-related genes)

Outcome:

Circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 levels in all children in whom it was measured.

Confounding variables:

Age at time of IGF/IGFBP measurement, sex, 10 principal components for population stratification.

Reference List

1 Rowlands M, Gunnell D, Harris R, Vatten LJ, Holly JMP, Martin RM: Circulating insulin-like growth factor peptides and prostate cancer risk: A systematic review and meta-analysis. Int J Cancer 2009;124:2416-2429.

2 Rowlands MA, Holly JMP, Gunnell D, Donovan J, Lane JA, Hamdy F, Neal DE, Oliver S, Smith GD, Martin RM: Circulating Insulin-Like Growth Factors and IGF-Binding Proteins in PSA-Detected Prostate Cancer: The Large Case-Control Study ProtecT. Cancer Res 2012;72:503-515.

3 Eeles RA, Kote-Jarai Z, Al Olama AA, et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet 2009;41:1116-1121.

4 Schumacher FR, Cheng I, Freedman ML, et al. A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians. Hum Mol Genet 2010;19:3089-3101.

5 Koutros S, Schumacher FR, Hayes RB, et al. Pooled Analysis of Phosphatidylinositol 3-Kinase Pathway Variants and Risk of Prostate Cancer. Cancer Res 2010;70:2389-2396.

6 Neuhausen SL, Slattery ML, Garner CP, Ding YC, Hoffman M, Brothman AR: Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk. Prostate 2005;64:168-174.

7 Ho GY, Melman A, Liu SM, Li M, Yu H, Negassa A, Burk RD, Hsing AW, Ghavamian R, Chua SC, Jr.: Polymorphism of the insulin gene is associated with increased prostate cancer risk. British Journal of Cancer 88(2):263-9, 2003.

8 Johansson M, Mckay JD, Stattin P, Canzian F, Boillot C, Wiklund F, Adami HO, Balter K, Gronberg H, Kaaks R: Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer. Int J Cancer 2007;120:539-542.

9 Cheng I, Stram DO, Penney KL, Pike M, Le ML, Kolonel LN, Hirschhorn J, Altshuler D, Henderson BE, Freedman ML: Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst 2006;98:123-134.

10 Gu F, Schumacher FR, Canzian F, Allen NE, et al. Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer. Cancer Epidemiology Biomarkers & Prevention 2010;19:2877-2887.

11 Hernandez W, Grenade C, Santos ER, Bonilla C, Ahaghotu C, Kittles RA: IGF-I and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans. Carcinogenesis 2007;28:2154-2159.

12 Wang LZ, Habuchi T, Tsuchiya N, et al. Insulin-like growth factor-binding protein-3 gene-202 A/C polymorphism is correlated with advanced disease status in prostate cancer. Cancer Res 2003;63:4407-4411.

13 Al-Zahrani A, Sandhu MS, Luben RN, et al. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 2006;15:1-10.

14 Terry KL, Tworoger SS, Gates MA, Cramer DW, Hankinson SE: Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk. Carcinogenesis 2009;30:2042-2046.

15 Kaplan RC, Petersen AK, Chen MH, et al. A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. Hum Mol Genet 2011.