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      Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population

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          Abstract

          Introduction

          Prostate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland.

          Methods

          The study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped.

          Results

          The mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 μg/l vs. 856.6±13.05 μg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07–9.37, p<0.01) was observed in 3 rd quartile (>853.0–973.9 μg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19–4.82, p = 0.015).

          Conclusion

          Our results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland.

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          Most cited references60

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          Germline mutations in HOXB13 and prostate-cancer risk.

          Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).
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            Indicators of zinc status at the population level: a review of the evidence.

            The role of zinc deficiency as an important cause of morbidity and impaired linear growth has prompted the need to identify indicators of population zinc status. Three indicators have been recommended - prevalence of zinc intakes below the estimated average requirement (EAR), percentage with low serum zinc concentrations, and percentage of children aged < 5 years who are stunted. This review outlines steps to estimate the prevalence of inadequate intakes, and confirm their validity based on the EARs set by International Zinc Nutrition Collaborative Group. Next, the appropriateness of serum zinc as a biochemical marker for population zinc status is confirmed by a summary of: (a) the response of serum zinc concentrations to zinc intakes; (b) usefulness of serum zinc concentrations to predict functional responses to zinc interventions; (c) relationship between initial serum zinc and change in serum zinc in response to interventions. Height- or length-for-age was chosen as the best functional outcome after considering the responses of growth, infectious diseases (diarrhoea, pneumonia), and developmental outcomes in zinc supplementation trials and correlation studies. The potential of other zinc biomarkers such as zinc concentrations in hair, cells, zinc-metalloenzymes, and zinc-binding proteins, such as metallothionein, is also discussed. Molecular techniques employing reverse transcriptase (RT)-polymerase chain reaction to measure mRNA in metallothionein and ZIP1 transporter hold promise, as do kinetic markers such as exchangeable zinc pools (EZP) and plasma zinc turnover rates. More research is needed to establish the validity, specificity, sensitivity, and feasibility of these new biomarkers, especially in community-settings.
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              Mutations in CHEK2 associated with prostate cancer risk.

              The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 July 2018
                2018
                : 13
                : 7
                : e0201065
                Affiliations
                [1 ] Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
                [2 ] Read-Gene S.A., Grzepnica, Poland
                [3 ] Strand Life Sciences, Bangalore, Karnataka, India
                [4 ] School of Biomedical Sciences, University of Newcastle, Newcastle, Australia
                [5 ] Division of Molecular Medicine, NSW Health Pathology, Newcastle, Australia
                [6 ] Independent laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: JL is CEO of Read-Gene S.A. The authors WM, MM are employees of Read-Gene S.A. KB, PB, GS, KD, TG, KP, CC, TH, JG, TD, RJS, AJ declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0001-8489-6665
                Article
                PONE-D-18-08754
                10.1371/journal.pone.0201065
                6056054
                30036379
                0a5e89e6-407f-4066-a5aa-0dc9cc66189c
                © 2018 Białkowska et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 March 2018
                : 7 July 2018
                Page count
                Figures: 0, Tables: 0, Pages: 11
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;
                Award ID: DEC-2012/07/N/NZ4/02433
                Award Recipient : Katarzyna Kaczmarek
                The project was financially supported by National Science Centre, grant no. DEC-2012/07/N/NZ4/02433. The funder did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder Read-Gene S.A. provided support in the form of salaries for authors WM, MM, JL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Medicine and Health Sciences
                Urology
                Prostate Diseases
                Prostate Cancer
                Physical Sciences
                Chemistry
                Chemical Elements
                Zinc
                Biology and Life Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Diagnostic Medicine
                Cancer Detection and Diagnosis
                Medicine and Health Sciences
                Oncology
                Cancer Detection and Diagnosis
                People and Places
                Population Groupings
                Ethnicities
                European People
                Slavic People
                Polish People
                People and places
                Geographical locations
                Europe
                European Union
                Poland
                Medicine and Health Sciences
                Oncology
                Cancer Risk Factors
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Genotyping
                Research and Analysis Methods
                Molecular Biology Techniques
                Genotyping
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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