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Allografting

Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan

Bone Marrow Transplantation volume 45, pages 1316–1324 (2010)Cite this article

Abstract

High-dose melphalan (HDM) is an essential component in the treatment of patients with multiple myeloma (MM). Few data are available regarding genetic polymorphisms associated with patient outcome or toxicity in this setting. To identify such polymorphisms, we performed a retrospective analysis, genotyping single nucleotide polymorphisms (SNPs) with the arrayed primer extension (APEX) technology in 169 patients having received HDM for MM. We analyzed 209 SNPs in 95 genes involved in drug metabolism, DNA repair, cell cycle and apoptosis. SNPs in ABCB1, CYP3A4 and TP53BP2 were associated with response to VAD induction therapy (P<0.01). SNPs in ALDH2, GSTT2 and BRCA1 were associated with response to HDM (P<0.01). Polymorphisms in CYP1A1, RAD51 and PARP were associated with disease progression whereas polymorphisms in ALDH2 and CYP1A1 were correlated with OS. Polymorphisms in BRCA1, CDKN1A and XRCC1 were associated with the occurrence of severe mucositis after HDM. These results suggest that SNPs of genes involved in drug metabolism or DNA repair could be used to distinguish MM patient subgroups with different toxicity/efficacy profiles.

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References

  1. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.

    Article  CAS  Google Scholar 

  2. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349: 2495–2502.

    Article  CAS  Google Scholar 

  3. Dasgupta RK, Adamson PJ, Davies FE, Rollinson S, Roddam PL, Ashcroft AJ et al. Polymorphic variation in GSTP1 modulates outcome following therapy for multiple myeloma. Blood 2003; 102: 2345–2350.

    Article  CAS  Google Scholar 

  4. Schilthuizen C, Broyl A, van der Holt B, de Knegt Y, Lokhorst H, Sonneveld P . Influence of genetic polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 genes on survival and therapy-related toxicity in multiple myeloma. Haematologica 2007; 92: 277–278.

    Article  Google Scholar 

  5. Vangsted A, Gimsing P, Klausen TW, Nexo BA, Wallin H, Andersen P et al. Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation. Int J Cancer 2007; 120: 1036–1045.

    Article  CAS  Google Scholar 

  6. Galmarini CM, Graham K, Thomas X, Calvo F, Rousselot P, El Jafaari A et al. Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia. Blood 2001; 98: 1922–1926.

    Article  CAS  Google Scholar 

  7. Gemignani F, Landi S, Vivant F, Zienolddiny S, Brennan P, Canzian F . A catalogue of polymorphisms related to xenobiotic metabolism and cancer susceptibility. Pharmacogenetics 2002; 12: 459–463.

    Article  CAS  Google Scholar 

  8. Landi S, Gemignani F, Gioia-Patricola L, Chabrier A, Canzian F . Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair. Biotechniques 2003; 35: 816–820, 822, 824–7.

    Article  CAS  Google Scholar 

  9. Maggini V, Buda G, Galimberti S, Conidi E, Giuliani N, Morabito F et al. Response to chemotherapy and tandem autologous transplantation of multiple myeloma patients and GSTP1 and TYMS polymorphisms. Leuk Res 2007; 16: 16.

    Google Scholar 

  10. Berenson JR, Ma HM, Vescio R . The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma. Semin Oncol 2001; 28: 626–633.

    Article  CAS  Google Scholar 

  11. Avet-Loiseau H, Li JY, Morineau N, Facon T, Brigaudeau C, Harousseau JL et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood 1999; 94: 2583–2589.

    CAS  PubMed  Google Scholar 

  12. Facon T, Avet-Loiseau H, Guillerm G, Moreau P, Genevieve F, Zandecki M et al. Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001; 97: 1566–1571.

    Article  CAS  Google Scholar 

  13. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 2007; 109: 3489–3495.

    Article  CAS  Google Scholar 

  14. Rothman KJ . No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–46.

    Article  CAS  Google Scholar 

  15. Buda G, Maggini V, Galimberti S, Martino A, Giuliani N, Morabito F et al. MDR1 polymorphism influences the outcome of multiple myeloma patients. Br J Haematol 2007; 137: 454–456.

    Article  CAS  Google Scholar 

  16. Jamroziak K, Balcerczak E, Panczyk M, Piaskowski S, Janus A, Cebula B et al. Pharmacogenetic analysis of polymorphisms in pharmacological pathway of vincristine, doxorubicine and dexamethasone (VAD regimen) to predict response in patients with multiple myeloma. Am Soc Hematol 2005; Abstract 104.

  17. Siegmund W, Ludwig K, Giessmann T, Dazert P, Schroeder E, Sperker B et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 2002; 72: 572–583.

    Article  CAS  Google Scholar 

  18. Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ . Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 2003; 13: 89–95.

    Article  CAS  Google Scholar 

  19. Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14: 1889–1896.

    Article  CAS  Google Scholar 

  20. Hu X, Xia H, Srivastava SK, Pal A, Awasthi YC, Zimniak P et al. Catalytic efficiencies of allelic variants of human glutathione S-transferase P1-1 toward carcinogenic anti-diol epoxides of benzo[c]phenanthrene and benzo[g]chrysene. Cancer Res 1998; 58: 5340–5343.

    CAS  PubMed  Google Scholar 

  21. Sato K . Glutathione transferases as markers of preneoplasia and neoplasia. Adv Cancer Res 1989; 52: 205–255.

    Article  CAS  Google Scholar 

  22. Kyosseva SV, Owens SM, Elbein AD, Karson CN . Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. Neuropsychopharmacology 2001; 24: 267–277.

    Article  CAS  Google Scholar 

  23. Yin Z, Ivanov VN, Habelhah H, Tew K, Ronai Z . Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res 2000; 60: 4053–4057.

    CAS  Google Scholar 

  24. Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS . The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood 2005; 106: 698–705.

    Article  CAS  Google Scholar 

  25. Chen Z, Yang J, Wang G, Song B, Li J, Xu Z . Attenuated expression of xeroderma pigmentosum group C is associated with critical events in human bladder cancer carcinogenesis and progression. Cancer Res 2007; 67: 4578–4585.

    Article  CAS  Google Scholar 

  26. Zhu Y, Yang H, Chen Q, Lin J, Grossman HB, Dinney CP et al. Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA Repair 2007; 6: 6.

    Google Scholar 

  27. Van Ness BG, Crowley JC, Ramos C, Grindle S, Rasmussen E, Hoering A et al. SNP genotypes show association with common toxicities during both VAD induction and high dose melphalan with autologous transplant support in Intergroup Trial S9321 for Myeloma: From the Bank on a Cure. Am Soc Hematol 2005; Abstract 3488.

  28. Sonneveld P, Schilthuizen C, Lokhorst H, Vellenga E, Raymakers R, de Knegt Y et al. Influence of genetic single nucleotide polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 genes on survival and treatment related toxicity in patients with multiple myeloma treated in the HOVON 24 Trial. Am Soc Hematol 2005; 111; Abstract 505.

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Acknowledgements

This work has been supported by a grant from Italian Ministry of Education, University and Research (MIUR) and the Alberta Heritage Foundation for Medical Research (TR). FG is an investigator financed by MIUR under the program ‘Rientro dei Cervelli.’

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Authors and Affiliations

  1. LCMT, Hospices Civils de Lyon, Lyon, France

    C Dumontet, A Plesa & J Troncy

  2. Inserm, U590, Lyon, France

    C Dumontet, A Plesa & J Troncy

  3. Genetics, University of Pisa, Pisa, Italy

    S Landi, I Bellini, R Barale & F Gemignani

  4. Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

    T Reiman, T Perry & L M Pilarski

  5. Genetics, IARC, Lyon, France

    S Tavtigian

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  1. C Dumontet
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  2. S Landi
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Correspondence to C Dumontet.

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Dumontet, C., Landi, S., Reiman, T. et al. Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan. Bone Marrow Transplant 45, 1316–1324 (2010). https://doi.org/10.1038/bmt.2009.335

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