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Myeloma

DNA methylation changes in multiple myeloma

Abstract

Using a candidate gene approach, we analyzed the methylation status of the promoter-associated CpG islands of 11 well-characterized tumor suppressor genes by methylation-specific polymerase chain reaction in five multiple myeloma (MM) cell lines and 56 patients with malignant plasma cell disorders. The frequency of aberrant methylation among the patient samples was 46.4% for SOCS-1, 35.7% for p16, 21.4% for E-cadherin, 12.5% for DAP kinase and p73, 1.8% for p15, MGMT as well as RARĪ², and 0% for TIMP-3, RASSF1A and hMLH1. We found at least one hypermethylated gene in 80.4% of the primary patient samples, while 33.9% harbored two or more hypermethylated genes. For the first time, we show that p73 may be hypermethylated in MM and thus be involved in the pathogenesis of plasma cell disorders. Hypermethylation of p16 at diagnosis was associated with a poorer prognosis. In patients with plasma cell leukemia, we found frequent simultaneous hypermethylation of p16, E-cadherin and DAP kinase. We conclude that aberrant methylation of tumor suppressor genes is a common event in malignant plasma cell disorders and that there is a correlation between methylation patterns and clinical characteristics in MM patients.

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References

  1. Hallek M, Bergsagel PL, Anderson KC . Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998; 91: 3ā€“21.

    CASĀ  PubMedĀ  Google ScholarĀ 

  2. Kastrinakis NG, Gorgoulis VG, Foukas PG, Dimopoulos MA, Kittas C . Molecular aspects of multiple myeloma. Ann Oncol 2000; 11: 1217ā€“1228.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  3. Kuehl WM, Bergsagel PL . Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002; 2: 175ā€“187.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  4. Baylin SB, Herman JG . DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168ā€“174.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Jones PA, Baylin SB . The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415ā€“428.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  6. Ng MH, Chung YF, Lo KW, Wickham NW, Lee JC, Huang DP . Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 1997; 89: 2500ā€“2506.

    CASĀ  PubMedĀ  Google ScholarĀ 

  7. Gonzalez M, Mateos MV, Garcia-Sanz R, Balanzategui A, Lopez-Perez R, Chillon MC et al. De novo methylation of tumor suppressor gene p16/INK4a is a frequent finding in multiple myeloma patients at diagnosis. Leukemia 2000; 14: 183ā€“187.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  8. Kramer A, Schultheis B, Bergmann J, Willer A, Hegenbart U, Ho AD et al. Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma. Leukemia 2002; 16: 1844ā€“1851.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  9. Mateos MV, Garcia-Sanz R, Lopez-Perez R, Moro MJ, Ocio E, Hernandez J et al. Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival. Br J Haematol 2002; 118: 1034ā€“1040.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  10. Ng MH, To KW, Lo KW, Chan S, Tsang KS, Cheng SH et al. Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma. Clin Cancer Res 2001; 7: 1724ā€“1729.

    CASĀ  PubMedĀ  Google ScholarĀ 

  11. Ng MH, Lau KM, Wong WS, To KW, Cheng SH, Tsang KS et al. Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non-functional variant transcript. Br J Haematol 2003; 123: 637ā€“645.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG . SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 2003; 101: 2784ā€“2788.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  13. Esteller M, Corn PG, Baylin SB, Herman JG . A gene hypermethylation profile of human cancer. Cancer Res 2001; 61: 3225ā€“3229.

    CASĀ  PubMedĀ  Google ScholarĀ 

  14. Issa JP . Decitabine. Curr Opin Oncol 2003; 15: 446ā€“451.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  15. Esteller M . CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 2002; 21: 5427ā€“5440.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Laird PW . Early detection: the power and the promise of DNA methylation markers. Nat Rev Cancer 2003; 3: 253ā€“266.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  17. Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 1999; 59: 798ā€“802.

    CASĀ  PubMedĀ  Google ScholarĀ 

  18. Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB et al. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation. Cancer Res 1999; 59: 3352ā€“3356.

    CASĀ  PubMedĀ  Google ScholarĀ 

  19. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 1995; 55: 5195ā€“5199.

    CASĀ  PubMedĀ  Google ScholarĀ 

  20. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 2001; 28: 29ā€“35.

    CASĀ  PubMedĀ  Google ScholarĀ 

  21. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG . Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999; 59: 793ā€“797.

    CASĀ  PubMedĀ  Google ScholarĀ 

  22. Cameron EE, Baylin SB, Herman JG . p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. Blood 1999; 94: 2445ā€“2451.

    CASĀ  PubMedĀ  Google ScholarĀ 

  23. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998; 95: 6870ā€“6875.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  24. Katzenellenbogen RA, Baylin SB, Herman JG . Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999; 93: 4347ā€“4353.

    CASĀ  PubMedĀ  Google ScholarĀ 

  25. Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001; 93: 691ā€“699.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  26. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC et al. 5ā€² CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995; 1: 686ā€“692.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D et al. Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst 2000; 92: 1303ā€“1307.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  28. Durie BG . Staging and kinetics of multiple myeloma. Semin Oncol 1986; 13: 300ā€“309.

    CASĀ  PubMedĀ  Google ScholarĀ 

  29. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821ā€“9826.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  30. Smiraglia DJ, Rush LJ, Fruhwald MC, Dai Z, Held WA, Costello JF et al. Excessive CpG island hypermethylation in cancer cell lines vs primary human malignancies. Hum Mol Genet 2001; 10: 1413ā€“1419.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  31. Melki JR, Vincent PC, Clark SJ . Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 1999; 59: 3730ā€“3740.

    CASĀ  PubMedĀ  Google ScholarĀ 

  32. Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM et al. DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 2217ā€“2224.

    CASĀ  PubMedĀ  Google ScholarĀ 

  33. Chen CY, Tsay W, Tang JL, Shen HL, Lin SW, Huang SY et al. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer 2003; 37: 300ā€“305.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  34. Rossi D, Capello D, Gloghini A, Franceschetti S, Paulli M, Bhatia K et al. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica 2004; 89: 154ā€“164.

    CASĀ  PubMedĀ  Google ScholarĀ 

  35. Guillerm G, Gyan E, Wolowiec D, Facon T, Avet-Loiseau H, Kuliczkowski K et al. p16(INK4a) and p15(INK4b) gene methylations in plasma cells from monoclonal gammopathy of undetermined significance. Blood 2001; 98: 244ā€“246.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  36. Guillerm G, Depil S, Wolowiec D, Quesnel B . Different prognostic values of p15INK4b and p16INK4a gene methylations in multiple myeloma. Haematologica 2003; 88: 476ā€“478.

    PubMedĀ  Google ScholarĀ 

  37. Depil S, Saudemont A, Quesnel B . SOCS-1 gene methylation is frequent but does not appear to have prognostic value in patients with multiple myeloma. Leukemia 2003; 17: 1678ā€“1679.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  38. Kawano S, Miller CW, Gombart AF, Bartram CR, Matsuo Y, Asou H et al. Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood 1999; 94: 1113ā€“1120.

    CASĀ  PubMedĀ  Google ScholarĀ 

  39. Martinez-Delgado B, Melendez B, Cuadros M, Jose Garcia M, Nomdedeu J, Rivas C et al. Frequent inactivation of the p73 gene by abnormal methylation or LOH in non-Hodgkin's lymphomas. Int J Cancer 2002; 102: 15ā€“19.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  40. Willemze R, Suciu S, Archimbaud E, Muus P, Stryckmans P, Louwagie EA et al. A randomized phase II study on the effects of 5-aza-2'-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase II study (06893). Leukemia 1997; 11 (Suppl 1): S24ā€“S27.

    PubMedĀ  Google ScholarĀ 

  41. Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M et al. Low-dose 5-aza-2ā€²-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18: 956ā€“962.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  42. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429ā€“2440.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  43. Kantarjian HM, O'Brien S, Cortes J, Giles FJ, Faderl S, Issa JP et al. Results of decitabine (5-aza-2ā€²deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 2003; 98: 522ā€“528.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

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Acknowledgements

We thank Sandra Mellen and Ingeborg Wiegand for expert technical assistance and Albert Esser for help with the statistical analysis. This work was supported by a grant from the Rheinisch-Westfaelische Technische Hochschule Aachen (START program) and the Samuel Waxman Cancer Research Foundation. JGH is a paid consultant to and receives research support from OncoMethylome Sciences. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Galm, O., Wilop, S., Reichelt, J. et al. DNA methylation changes in multiple myeloma. Leukemia 18, 1687ā€“1692 (2004). https://doi.org/10.1038/sj.leu.2403434

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