Investigating the genetic basis of periprostatic adipose tissue (PPAT) and the causal role in aggressive/advanced prostate cancer
Year: 2026
Type: other
Abstract: Project Summary Obesity is one of the few established risk factors for aggressive prostate cancer (PCa), yet the mechanisms underlying this association remain unclear.1-4 Periprostatic adipose tissue (PPAT) is a visceral fat depot in direct anatomical proximity to the prostate and may promote tumour development through local inflammatory and metabolic pathways.5 This project will conduct the first genome-wide association study (GWAS) of PPAT and apply Mendelian randomisation (MR) to assess whether PPAT is causally related to advanced PCa or aggressive PCa. Imaging-derived PPAT phenotypes from UK Biobank and AGES-Reykjavik will be integrated with PCa GWAS data from the PRACTICAL consortium.6-8 There are different ways of measuring PPAT, including by ultrasound9, magnetic resonance imaging (MRI)10-12 or by computer-tomography (CT)13,14. UK Biobank is a prospective population-based study of ~500,000 individuals recruited across the UK from 2006-2010 with follow up data on a sub-population of these individuals, which includes MRI derived imaging data available for 27,748 male individuals.15 Robust sensitivity analyses, including multivariable MR to account for total visceral adipose tissue (VAT) as a measure of general adiposity, and a contrast outcome (endometrial cancer) will be used to strengthen causal inference in line with World Cancer Research Fund (WCRF) methodological guidance.2 If we find evidence of a causal effect of PPAT on PCa, we will perform a phenome-wide association analysis (PheWAS) to investigate any potential pleiotropic pathways, which could represent horizontal or vertical pleiotropy. If we can identify a potential biological pathway either from the literature or our own analyses, we will apply MR to investigate the causal role (if any) of lifestyle/metabolic traits which leads to increased PPAT. This Statistical Analysis Plan (SAP) describes the pre-specified analyses for the investigation of PPAT as a causal risk factor for prostate cancer using GWAS an MR. This SAP is aligned with WCRF methodological expectations, emphasising causal inference, transparency, reproducibility and robustness. References 1 Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424, doi:10.3322/caac.21492 (2018). 2 Clinton, S. K., Giovannucci, E. L. & Hursting, S. D. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr 150, 663-671, doi:10.1093/jn/nxz268 (2020). 3 Allott, E. H. & Hursting, S. D. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr Relat Cancer 22, R365-386, doi:10.1530/erc-15-0400 (2015). 4 Research, W. C. R. F. A. I. f. C. Diet, Nutrition, Physical Activity and Cancer: A Global Perspective. (2018). 5 Laurent, V. et al. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nature Communications 7, 10230, doi:10.1038/ncomms10230 (2016). 6 Littlejohns, T. J. et al. The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions. Nature Communications 11, 2624, doi:10.1038/s41467-020-15948-9 (2020). 7 Harris, T. B. et al. Age, Gene/Environment Susceptibility–Reykjavik Study: Multidisciplinary Applied Phenomics. American Journal of Epidemiology 165, 1076-1087, doi:10.1093/aje/kwk115 (2007). 8 Schumacher, F. R. et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. 9 Bhindi, B. et al. Measurement of peri-prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer. BJU Int 110, 980-986, doi:10.1111/j.1464-410X.2012.10957.x (2012). 10 Dahran, N., Szewczyk-Bieda, M., Wei, C., Vinnicombe, S. & Nabi, G. Normalized periprostatic fat MRI measurements can predict prostate cancer aggressiveness in men undergoing radical prostatectomy for clinically localised disease. Sci Rep 7, 4630, doi:10.1038/s41598-017-04951-8 (2017). 11 Salji, M. et al. Peri-prostatic Fat Volume Measurement as a Predictive Tool for Castration Resistance in Advanced Prostate Cancer. Eur Urol Focus 4, 858-866, doi:10.1016/j.euf.2017.01.019 (2018). 12 Gregg, J. R. et al. The Association of Periprostatic Fat and Grade Group Progression in Men with Localized Prostate Cancer on Active Surveillance. J Urol 205, 122-128, doi:10.1097/ju.0000000000001321 (2021). 13 van Roermund, J. G. et al. Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients. BJU Int 107, 1775-1779, doi:10.1111/j.1464-410X.2010.09811.x (2011). 14 Allott, E. H. et al. Racial differences in adipose tissue distribution and risk of aggressive prostate cancer among men undergoing radiotherapy. Cancer Epidemiol Biomarkers Prev 23, 2404-2412, doi:10.1158/1055-9965.Epi-14-0236 (2014). 15 Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data.
Source: Open Science Framework
Authors: Amy Dawes, Tom R Gaunt, Emma Allott, Richard Martin
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212180912