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Identifying proteom...
Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics
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- Desai, Trishna A. (författare)
- Univ Oxford, Canc Epidemiol Unit, Oxford Populat Hlth, Oxford, England.
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- Hedman, Asa K. (författare)
- Pfizer Worldwide Res Dev & Med, External Sci & Innovat, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
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- Dimitriou, Marios (författare)
- Pfizer Worldwide Res Dev & Med, External Sci & Innovat, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
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- Koprulu, Mine (författare)
- Univ Cambridge, MRC Epidemiol Unit, Cambridge, England.
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- Figiel, Sandy (författare)
- Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.
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- Yin, Wencheng (författare)
- Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.
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- Johansson, Mattias (författare)
- Int Agcy Res Canc IARC WHO, Genom Epidemiol Branch, Lyon, France.
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- Watts, Eleanor L. (författare)
- NCI, Div Canc Epidemiol & Genet, Metab Epidemiol Branch, Rockville, MD USA.
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Atkins, Joshua R. (författare)
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- Sokolov, Aleksandr V. (författare)
- Uppsala universitet,Funktionell farmakologi och neurovetenskap
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- Schiöth, Helgi (författare)
- Uppsala universitet,Funktionell farmakologi och neurovetenskap
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- Gunter, Marc J. (författare)
- Int Agcy Res Canc IARC WHO, Genom Epidemiol Branch, Lyon, France.
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- Tsilidis, Konstantinos K. (författare)
- Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, St Marys Campus,Norfolk Pl, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina, Greece.
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- Martin, Richard M. (författare)
- Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, England.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, England.;Hosp Bristol & Weston NHS Fdn Trust, NIHR Bristol Biomed Res Ctr, Bristol, England.;Univ Bristol, Bristol, England.
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- Pietzner, Maik (författare)
- Charite, Computat Med, Berlin Inst HealthHlth BIH, Univ Med Berlin, Berlin, Germany.
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- Langenberg, Claudia (författare)
- Queen Mary Univ London, Precis Healthcare Univ Res Inst, London, England.
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- Mills, Ian G. (författare)
- Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.
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- Lamb, Alastair D. (författare)
- Pfizer Worldwide Res Dev & Med, External Sci & Innovat, Stockholm, Sweden.;Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.
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- Maelarstig, Anders (författare)
- Pfizer Worldwide Res Dev & Med, External Sci & Innovat, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
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- Key, Tim J. (författare)
- Univ Oxford, Canc Epidemiol Unit, Oxford Populat Hlth, Oxford, England.
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- Travis, Ruth C. (författare)
- Univ Oxford, Canc Epidemiol Unit, Oxford Populat Hlth, Oxford, England.
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- Smith-Byrne, Karl (författare)
- Univ Oxford, Canc Epidemiol Unit, Oxford Populat Hlth, Oxford, England.
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Univ Oxford, Canc Epidemiol Unit, Oxford Populat Hlth, Oxford, England Pfizer Worldwide Res Dev & Med, External Sci & Innovat, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. (creator_code:org_t)
- Elsevier, 2024
- 2024
- Engelska.
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 105
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Background Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis- pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple -testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate -speci fi c tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. Findings We identi fi ed 20 proteins genetically linked to prostate cancer risk (14 for overall [8 speci fi c], 7 for aggressive [3 speci fi c], and 8 for early onset disease [2 speci fi c]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54 - 2.93], PYY [OR = 1.87, 95% CI: 1.43 - 2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73 - 0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99 - 4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67 - 0.86] and TPM3 [OR = 0.47, 95% CI: 0.34 - 0.64]. We con fi rmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80 - 0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82 - 0.86] and early onset disease [OR = 0.71, 95% CI: 0.68 - 0.74]. Using spatial transcriptomics data, we identi fi ed MSMB as the genome-wide top -most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had fi ve -fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. Interpretation Our fi ndings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added bene fi t of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Proteins
- Proteomics
- -Omics
- Mendelian randomisation
- Cancer
- Genetic epidemiology
- Spatial transcriptomics
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Desai, Trishna A ...
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Hedman, Asa K.
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Dimitriou, Mario ...
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Koprulu, Mine
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Figiel, Sandy
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Yin, Wencheng
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visa fler...
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Johansson, Matti ...
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Watts, Eleanor L ...
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Atkins, Joshua R ...
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Sokolov, Aleksan ...
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Schiöth, Helgi
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Gunter, Marc J.
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Tsilidis, Konsta ...
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Martin, Richard ...
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Pietzner, Maik
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Langenberg, Clau ...
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Mills, Ian G.
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Lamb, Alastair D ...
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Maelarstig, Ande ...
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Key, Tim J.
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Travis, Ruth C.
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Smith-Byrne, Kar ...
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