Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Eleanor L. Watts *, Georgina K. Fensom , Karl Smith Byrne , Aurora Perez-Cornago , Naomi E. Allen , Anika Knuppel , Marc J. Gunter , Michael V. Holmes , Richard M Martin, Neil Murphy, Konstantinos K. Tsilidis , Bu B. Yeap , Timothy J. Key , Ruth C. Travis

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199,698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79,148 cases and 61,106 controls). We used cis- and all (cis and trans) SNP MR approaches. 5,402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment=1.15,1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment=0.95,0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.
Original languageEnglish
Pages (from-to)2274-2288
Number of pages15
JournalInternational Journal of Cancer
Volume148
Issue number9
Early online date30 Nov 2020
DOIs
Publication statusPublished - 1 May 2021

Bibliographical note

Funding Information:
The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers and Tattersall's. EAO, DMK and EMK acknowledge the Intramural Program of the National Human Genome Research Institute for their support.

Funding Information:
This research has been conducted using the UK Biobank Resource under application number 3282 and data from the PRACTICAL consortium, CRUK, BPC3, CAPS and PEGASUS.This work was supported by Cancer Research UK (grant numbers C8221/A19170, C8221/A20986 and C8221/A29017). ELW was supported by the Nuffield Department of Population Health Early Career Research Fellowship. AK is supported by the Wellcome Trust (LEAP 205212/Z/16/Z). APC is supported by a Cancer Research UK Population Research Fellowship (C60192/A28516). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. RMM was supported by a Cancer Research UK (C18281/A19169) programme grant (the Integrative Cancer Epidemiology Programme) and is part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by the Medical Research Council (MC_UU_12013/1, MC_UU_12013/2, and MC_UU_12013/3) and the University of Bristol. RMM is also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, which is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. KKT was funded by the Small Research Teams funding programme from the Hellenic Republic, Ministry of Education.

Funding Information:
CAPS GWAS study was supported by the Swedish Cancer Foundation (Grant No 09‐0677, 11‐484, 12‐823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org ), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (Grant No K2010‐70X‐20430‐04‐3, 2014‐2269).

Funding Information:
We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.

Funding Information:
British Heart Foundation, Grant/Award Number: FS/18/23/33512; Cancer Research UK, Grant/Award Numbers: C18281/A19169, C60192/A28516, C8221/A19170, C8221/A20986, C8221/A29017; Hellenic Republic, Ministry of Education; Medical Research Council, Grant/Award Numbers: MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/3; Nuffield Department of Population Health, Grant/Award Number: Early Career Research Fellowship; Wellcome Trust, Grant/Award Number: LEAP 205212/Z/16/Z Funding information

Funding Information:
PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

Funding Information:
Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher).

Funding Information:
The Prostate cancer genome‐wide association analyses are supported by the Canadian Institutes of Health Research, European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH‐F2‐2009‐223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post‐Cancer GWAS initiative grant: No. 1 U19 CA 148537‐01 (the GAME‐ON initiative).

Funding Information:
The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01‐CA98233 to D.J.H., U01‐CA98710 to S.M.G., U01‐CA98216 to E.R., and U01‐CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics).

Funding Information:
Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH‐F2‐2009‐223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post‐Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME‐ON initiative), the Department of Defence (W81XWH‐10‐1‐0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund.

Publisher Copyright:
© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Keywords

  • prostate cancer
  • testosterone
  • IGF-I
  • prospective analysis
  • Mendelian randomization

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