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Single-nucleotide polymorphisms in DNMT3B gene and DNMT3B mRNA expression in association with prostate cancer mortality

Prostate Cancer and Prostatic Diseases volume 22, pages 284–291 (2019)Cite this article

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Abstract

Background

Germline variants in DNA methyltransferase 3B (DNMT3B) may influence DNMT3B enzymatic activity, which, in turn, may affect cancer aggressiveness by altering DNA methylation.

Methods

The study involves two Italian cohorts (NTAT cohort, n = 157, and 1980s biopsy cohort, n = 182) and two U.S. cohorts (Health Professionals Follow-Up Study, n = 214, and Physicians’ Health Study, n = 298) of prostate cancer (PCa) patients, and a case–control study of lethal (n = 113) vs indolent (n = 290) PCa with DNMT3B mRNA expression data nested in the U.S. cohorts. We evaluated the association between: three selected DNMT3B variants and global DNA methylation using linear regression in the NTAT cohort, the three DNMT3B variants and PCa mortality using Cox proportional hazards regression in all cohorts, and DNMT3B expression and lethal PCa using logistic regression, with replication in publicly available databases (TCGA, n = 492 and MSKCC, n = 140).

Results

The TT genotype of rs1569686 was associated with LINE-1 hypomethylation in tumor tissue (β = −2.71, 95% CI: −5.41, −0.05). There was no evidence of association between DNMT3B variants and PCa mortality. DNMT3B expression was consistently associated with lethal PCa in the two U.S. cohorts (3rd vs 1st tertile, combined cohorts: OR = 2.04, 95% CI: 1.13, 3.76); the association was replicated in TCGA and MSKCC data (3rd vs 1st tertile, TCGA: HR = 3.00, 95% CI: 1.78, 5.06; MSKCC: HR = 2.22, 95% CI: 1.01, 4.86).

Conclusions

Although there was no consistent evidence of an association between DNMT3B variants and PCa mortality, the TT genotype of rs1569686 was associated with LINE-1 hypomethylation in tumor tissue and DNMT3B mRNA expression was associated with an increased risk of lethal PCa.

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Acknowledgements

The study was partially funded by the Italian Association for Cancer Research (AIRC); LR was partially supported by a Fulbright Research Scholar fellowship.

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Authors and Affiliations

  1. Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

    Renata Zelic

  2. Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy

    Valentina Fiano, Chiara Grasso, Morena Trevisan, Laura De Marco, Daniela Zugna & Lorenzo Richiardi

  3. Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA

    Ericka M. Ebot, Sarah Coseo Markt, Lorelei A. Mucci & Lorenzo Richiardi

  4. Division of Pathology, A.O.U. Città della Salute e della Scienza Hospital, Turin, Italy

    Luisa Delsedime

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Correspondence to Renata Zelic.

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Zelic, R., Fiano, V., Ebot, E.M. et al. Single-nucleotide polymorphisms in DNMT3B gene and DNMT3B mRNA expression in association with prostate cancer mortality. Prostate Cancer Prostatic Dis 22, 284–291 (2019). https://doi.org/10.1038/s41391-018-0102-5

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