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Methylation status of nine tumor suppressor genes in multiple myeloma

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Abstract

Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a, 42.8%; p15 INK4b, 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RARβ, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P < 0.001) and RARβ (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RARβ (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P < 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RARβ hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.

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Acknowledgments

We are grateful to Dr. Héctor N Seuánez (INCa - UFRJ, Brazil) for critical review of this manuscript. We thank Dr. Ladetto, Alberto Rocci (University of Torino, Italy) and Dr. Introna (Mario Negri Institute, Milan, Italy) for providing the cell lines. We thank the Instituto Nacional de Câncer (INCa), Fundação Ary Frauzino (FAF), and SwissBridge Foundation for their financial support. The work was supported in part by the Conselho Nacional de Pesquisas - CNPq - Brazil and Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP - Brazil.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    Esteban Braggio, Maria E. Gouveia & Ilana Zalcberg Renault

  2. Hematology Service, Department of Internal Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Angelo Maiolino, Roberto Magalhães, João T. Souto Filho, Márcia Garnica & Marcio Nucci

  3. Laboratory of Molecular Biology, CEMO, INCa, Praça da Cruz Vermelha 23, 6th Floor, Rio de Janeiro, RJ, 20230-130, Brazil

    Ilana Zalcberg Renault

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  1. Esteban Braggio
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Correspondence to Ilana Zalcberg Renault.

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Braggio, E., Maiolino, A., Gouveia, M.E. et al. Methylation status of nine tumor suppressor genes in multiple myeloma. Int J Hematol 91, 87–96 (2010). https://doi.org/10.1007/s12185-009-0459-2

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  • DOI: https://doi.org/10.1007/s12185-009-0459-2

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