Victoria Wang1, Milan S Geybels2,3, Kristina M Jordahl2, Travis Gerke4,5, Anis Hamid6, Kathryn L Penney5,7, Sarah C Markt5,6, Matthew Freedman8, Mark Pomerantz8, Gwo-Shu M Lee8, Huma Rana8, Daniela Börnigen9,10,11, Timothy R Rebbeck5, Curtis Huttenhower10,11, Ros A Eeles12,13, Janet L Stanford2, Practical Consortium14, Sonja I Berndt15, Frank Claessens16, Karina D Sørensen17, Jong Y Park18, Ana Vega19, Nawaid Usmani20, Lorelei Mucci5, Christopher J Sweeney8. 1. Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 2. Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, USA. 3. Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands. 4. Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA. 5. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 6. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA. 7. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 8. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA. 9. University Medical Center Hamburg-Eppendorf, Bioinformatics Core, Hamburg, Germany. 10. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA. 11. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 12. Oncogenetics, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. 13. The Royal Marsden NHS Foundation Trust, London, UK. 14. Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome. 15. Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA. 16. Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 17. Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark. 18. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA. 19. Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain. 20. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
Abstract
BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
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