The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

K Smith Byrne¹, P N Appleby¹, T J Key¹, M V Holmes², G K Fensom³, A Agudo⁴, E Ardanaz⁵, H Boeing⁶, H B Bueno-de-Mesquita⁷, M D Chirlaque⁸, R Kaaks⁹, N Larrañaga¹⁰, D Palli¹¹, A Perez-Cornago¹, J R Quirós¹², F Ricceri¹³, M J Sánchez¹⁴, G Tagliabue¹⁵, K K Tsilidis¹⁶, R Tumino¹⁷, R T Fortner⁹, P Ferrari¹⁸; PRACTICAL Consortium; E Riboli¹⁹, H Lilja²⁰, R C Travis¹

Affiliations

¹ Cancer Epidemiology Unit.
² Medical Research Council Population Health Research Unit, University of Oxford, Oxford; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Oxford; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³ Cancer Epidemiology Unit. Electronic address: georgina.fensom@ndph.ox.ac.uk.
⁴ Unit of Nutrition and Cancer, Catalan Institute of Oncology-IDIBELL, Barcelona.
⁵ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Navarra Public Health Institute, Pamplona; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
⁶ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
⁷ Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Department of Epidemiology, IMIB-Arrixaca, Murcia; Department of Health and Social Sciences, University of Murcia, Murcia, Spain.
⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Public Health Division of Gipuzkoa, Regional Government of the Basque Country, Vitoria-Gasteiz, Spain.
¹¹ Cancer Risk Factors and Life-style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
¹² Public Health Directorate, Asturias, Spain.
¹³ Unit of Epidemiology, Regional Health Service Azienda Sanitaria Locale Torino 3 (ASL TO3), Grugliasco; Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy.
¹⁴ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
¹⁵ Department of Preventative and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁷ Cancer Registry and Histopathology Unit, "Civic M.P. Arezzo" Hospital, Ragusa, Italy.
¹⁸ Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
¹⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁰ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Translational Medicine, Lund University, Malmö, Sweden.

PMID: 31089709
PMCID: PMC6594452
DOI: 10.1093/annonc/mdz121

Observational Study

The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

K Smith Byrne et al. Ann Oncol. 2019.

. 2019 Jun 1;30(6):983-989.

doi: 10.1093/annonc/mdz121.

Authors

Affiliations

¹ Cancer Epidemiology Unit.
² Medical Research Council Population Health Research Unit, University of Oxford, Oxford; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Oxford; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³ Cancer Epidemiology Unit. Electronic address: georgina.fensom@ndph.ox.ac.uk.
⁴ Unit of Nutrition and Cancer, Catalan Institute of Oncology-IDIBELL, Barcelona.
⁵ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Navarra Public Health Institute, Pamplona; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
⁶ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
⁷ Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Department of Epidemiology, IMIB-Arrixaca, Murcia; Department of Health and Social Sciences, University of Murcia, Murcia, Spain.
⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Public Health Division of Gipuzkoa, Regional Government of the Basque Country, Vitoria-Gasteiz, Spain.
¹¹ Cancer Risk Factors and Life-style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
¹² Public Health Directorate, Asturias, Spain.
¹³ Unit of Epidemiology, Regional Health Service Azienda Sanitaria Locale Torino 3 (ASL TO3), Grugliasco; Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy.
¹⁴ CIBER of Epidemiology and Public Health (CIBERESP), Madrid; Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
¹⁵ Department of Preventative and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁷ Cancer Registry and Histopathology Unit, "Civic M.P. Arezzo" Hospital, Ragusa, Italy.
¹⁸ Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
¹⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁰ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Translational Medicine, Lund University, Malmö, Sweden.

PMID: 31089709
PMCID: PMC6594452
DOI: 10.1093/annonc/mdz121

Abstract

Background: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods.

Patients and methods: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method.

Results: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP.

Conclusions: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.

Keywords: EPIC cohort; Mendelian randomization; microseminoprotein-beta; prospective study; prostate cancer; prostate-specific antigen.

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References

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The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

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The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

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