A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer

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  • Victoria Wang, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • ,
  • Milan S Geybels, Fred Hutchison Cancer Research Center
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  • Kristina M Jordahl, Fred Hutchison Cancer Research Center
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  • Travis Gerke, Moffitt Cancer Center
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  • Anis Hamid, Case Western Reserve Univ, Case Western Reserve University, Dept Surg
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  • Kathryn L Penney, Harvard TH Chan Sch Publ Hlth, Harvard T.H. Chan School of Public Health
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  • Sarah C Markt, Harvard TH Chan Sch Publ Hlth, Harvard T.H. Chan School of Public Health
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  • Matthew Freedman, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • ,
  • Mark Pomerantz, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • ,
  • Gwo-Shu M Lee, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • ,
  • Huma Rana, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • ,
  • Daniela Börnigen, University Medical Center Hamburg-Eppendorf
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  • Timothy R Rebbeck, Harvard TH Chan Sch Publ Hlth, Harvard T.H. Chan School of Public Health
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  • Curtis Huttenhower, Harvard Med Sch, Harvard University, Harvard Medical School, Dept Psychiat
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  • Ros A Eeles, The Royal Marsden / The Institute of Cancer Research National Institute for Health Research Biomedical Research Centre, London, UK.
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  • Janet L Stanford, Fred Hutchison Cancer Research Center
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  • Practical Consortium, Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL consortium)
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  • Sonja I Berndt, National Institute of Health's National Cancer Institute: Quantitative Imaging Network
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  • Frank Claessens, Molecular Endocrinology Laboratory, Odense University Hospital
  • ,
  • Karina D Sørensen
  • Jong Y Park, Moffitt Cancer Center
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  • Ana Vega, Fundación Pública Galega de Medicina Xenómica-SERGAS
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  • Nawaid Usmani, Univ Alberta, University of Alberta, Dept Psychiat
  • ,
  • Lorelei Mucci, Harvard TH Chan Sch Publ Hlth, Harvard T.H. Chan School of Public Health
  • ,
  • Christopher J Sweeney, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.

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.

OriginalsprogEngelsk
TidsskriftThe Prostate
Vol/bind81
Nummer10
Sider (fra-til)683-693
Antal sider11
ISSN0270-4137
DOI
StatusUdgivet - jul. 2021

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