Mp05-19 Polygenetic Risk Score for Prostate Cancer Is Associated With Lipopolysaccharide Pathway in Gut Microbiome

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP05)1 May 2024MP05-19 POLYGENETIC RISK SCORE FOR PROSTATE CANCER IS ASSOCIATED WITH LIPOPOLYSACCHARIDE PATHWAY IN GUT MICROBIOME Koji Hatano, Yoshihiko Tomofuji, Makoto Matsushita, Toshiki Oka, Daisuke Motooka, Saizo Fujimoto, Junya Hata, Akira Tsujimura, Wataru Obara, Shota Nakamura, Hirotsugu Uemura, Yukinori Okada, Norio Nonomura, and Kazutoshi Fujita Koji HatanoKoji Hatano , Yoshihiko TomofujiYoshihiko Tomofuji , Makoto MatsushitaMakoto Matsushita , Toshiki OkaToshiki Oka , Daisuke MotookaDaisuke Motooka , Saizo FujimotoSaizo Fujimoto , Junya HataJunya Hata , Akira TsujimuraAkira Tsujimura , Wataru ObaraWataru Obara , Shota NakamuraShota Nakamura , Hirotsugu UemuraHirotsugu Uemura , Yukinori OkadaYukinori Okada , Norio NonomuraNorio Nonomura , and Kazutoshi FujitaKazutoshi Fujita View All Author Informationhttps://doi.org/10.1097/01.JU.0001008740.27639.cc.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recently, genome-wide association studies (GWAS) have uncovered genetic predisposition to prostate cancer (PCa). Host genetic factors play a significant role in influencing microbial taxa variation. The aim of this study was to evaluate the association between polygenic risk scores (PRSs) for PCa and the gut microbiota at the levels of species, genes, and bacterial metabolic pathways. METHODS: Rectal swab samples were collected from 330 Japanese men suspected of PCa before prostate biopsies. Men with inadequate samples or antibiotic users were excluded. Two large-scale GWAS datasets, Biobank Japan and PRACTICAL consortium were utilized for constructing PRS. Shotgun metagenome sequencing was performed to identify the six taxonomic levels (L2: phyla, L3: classes, L4: orders, L5: families, L6: genera, and L7: species) and genes in the gut microbiota. Gene Set Enrichment Analysis (GSEA) was applied to the microbial gene-PRS association analysis. We used prostate-specific Pten-knockout mice [Pb-Cre+;Pten(fl/fl)] with a C57BL/6 genetic background as the PCa mouse model. RESULTS: A total of 166 men were eligible for analysis, including 60 healthy controls (HC) and 106 PCa patients. In this study, all the individuals were estimated to be of East Asian ancestry, based on the principal component analysis with the samples of the 1000 Genome Project dataset. PRS was consistently higher in the PCa group compared to the HC group. In the case-control analysis of the gut microbiome, both in the bacterial taxa and microbial genes, no significant associations with PCa were observed. The GSEA focused on pathways containing 50 or more detected KEGG genes but less than 30,000. As a result, 133 pathways were subjected to analysis, of which 18 pathways exhibited significant associations with PCa. In this study, particular attention was given to the lipopolysaccharide (LPS) synthesis pathway, which ranked second in terms of enrichment. In the PCa mouse model, gut dysbiosis induced by a high-fat diet resulted in elevated LPS levels, whereas inhibition of LPS/Toll-like receptor 4 signaling suppressed tumor growth. Notably, significant associations between PRS and the LPS synthesis pathway were observed (p=4.8×10-8). CONCLUSIONS: This study has unveiled a connection between PRSs linked to PCa and the LPS pathway within the gut microbiome. The findings suggest a correlation between a host's genetic predisposition to PCa and the metabolic pathways of the gut microbiota. Source of Funding: This research was supported by the Japan Society for the Promotion of Science KAKENHI, grant number 22H03212 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e50 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Koji Hatano More articles by this author Yoshihiko Tomofuji More articles by this author Makoto Matsushita More articles by this author Toshiki Oka More articles by this author Daisuke Motooka More articles by this author Saizo Fujimoto More articles by this author Junya Hata More articles by this author Akira Tsujimura More articles by this author Wataru Obara More articles by this author Shota Nakamura More articles by this author Hirotsugu Uemura More articles by this author Yukinori Okada More articles by this author Norio Nonomura More articles by this author Kazutoshi Fujita More articles by this author Expand All Advertisement PDF downloadLoading ...