Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Inherited genetic susceptibility to multiple myeloma

Leukemia volume 28, pages 518–524 (2014)Cite this article

Subjects

Abstract

Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Morgan GJ, Davies FE, Linet M . Myeloma aetiology and epidemiology. Biomed Pharmacother 2002; 56: 223–234.

    CAS  PubMed  Google Scholar 

  2. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113: 5412–5417.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Landgren O, Weiss BM . Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia 2009; 23: 1691–1697.

    CAS  PubMed  Google Scholar 

  5. Soderberg KC, Kaprio J, Verkasalo PK, Pukkala E, Koskenvuo M, Lundqvist E et al. Overweight, obesity and risk of haematological malignancies: a cohort study of Swedish and Finnish twins. Eur J Cancer 2009; 45: 1232–1238.

    PubMed  Google Scholar 

  6. Ruder AM, Hein MJ, Hopf NB, Waters MA . Mortality among 24 865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: A ten-year update. Int J Hyg Environ Health 2013; 13, pii: S1438-4639 00060–00066.

    Google Scholar 

  7. Lindqvist EK, Goldin LR, Landgren O, Blimark C, Mellqvist UH, Turesson I et al. Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study. Blood 2011; 118: 6284–6291.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Altieri A, Chen B, Bermejo JL, Castro F, Hemminki K . Familial risks and temporal incidence trends of multiple myeloma. Eur J Cancer 2006; 42: 1661–1670.

    PubMed  Google Scholar 

  9. Bourguet CC, Grufferman S, Delzell E, DeLong ER, Cohen HJ . Multiple myeloma and family history of cancer. A case-control study. Cancer 1985; 56: 2133–2139.

    CAS  PubMed  Google Scholar 

  10. Ogmundsdottir HM, Einarsdottir HK, Steingrimsdottir H, Haraldsdottir V . Familial predisposition to monoclonal gammopathy of unknown significance, Waldenstrom's macroglobulinemia, and multiple myeloma. Clin Lymphoma Myeloma 2009; 9: 27–29.

    PubMed  Google Scholar 

  11. Ogmundsdottir HM, Haraldsdottirm V, Johannesson GM, Olafsdottir G, Bjarnadottir K, Sigvaldason H et al. Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families. Haematologica 2005; 90: 66–71.

    PubMed  Google Scholar 

  12. Camp NJ, Werner TL, Cannon-Albright LA . Familial myeloma. N Engl J Med 2008; 359: 1734–1735, author reply 1735.

    CAS  PubMed  Google Scholar 

  13. Dilworth D, Liu L, Stewart AK, Berenson JR, Lassam N, Hogg D . Germline CDKN2A mutation implicated in predisposition to multiple myeloma. Blood 2000; 95: 1869–1871.

    CAS  PubMed  Google Scholar 

  14. Eriksson M, Karlsson M . Occupational and other environmental factors and multiple myeloma: a population based case-control study. Br J Ind Med 1992; 49: 95–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Eriksson M, Hallberg B . Familial occurrence of hematologic malignancies and other diseases in multiple myeloma: a case-control study. Cancer Causes Control 1992; 3: 63–67.

    CAS  PubMed  Google Scholar 

  16. Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 2009; 114: 791–795.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 2009; 114: 785–790.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brown LM, Linet MS, Greenberg RS, Silverman DT, Hayes RB, Swanson GM et al. Multiple myeloma and family history of cancer among blacks and whites in the US. Cancer 1999; 85: 2385–2390.

    CAS  PubMed  Google Scholar 

  19. Linet MS, McLaughlin JK, Harlow SD, Fraumeni JF . Family history of autoimmune disorders and cancer in multiple myeloma. Int J Epidemiol 1988; 17: 512–513.

    CAS  PubMed  Google Scholar 

  20. Jain M, Cook GM, Davis FG, Grace MG, Howe GR, Miller AB . A case-control study of diet and colo-rectal cancer. Int J Cancer 1980; 26: 757–768.

    CAS  PubMed  Google Scholar 

  21. Lynch HT, Watson P, Tarantolo S, Wiernik PH, Quinn-Laquer B, Isgur Bergsagel K et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol 2005; 23: 685–693.

    CAS  PubMed  Google Scholar 

  22. Grosbois B, Jego P, Attal M, Payen C, Rapp MJ, Fuzibet JG et al. Familial multiple myeloma: report of fifteen families. Br J Haematol 1999; 105: 768–770.

    CAS  PubMed  Google Scholar 

  23. Sobol H, Vey N, Sauvan R, Philip N, Noguchi T, Eisinger F . Re: familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst 2002; 94: 461–462, author reply 463.

    PubMed  Google Scholar 

  24. Jain M, Ascensao J, Schechter GP . Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009; 84: 34–38.

    PubMed  Google Scholar 

  25. Lynch HT, Thome SD . Familial multiple myeloma. Blood 2009; 114: 749–750.

    CAS  PubMed  Google Scholar 

  26. Lynch HT, Ferrara K, Barlogie B, Coleman EA, Lynch JF, Weisenburger D et al. Familial myeloma. N Engl J Med 2008; 359: 152–157.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Landgren O, Rajkumar SV, Pfeiffer RM, Kyle RA, Katzmann JA, Dispenzieri A et al. Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women. Blood 2010; 116: 1056–1059.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Greenberg AJ, Vachon CM, Rajkumar SV . Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites. Leukemia 2011; 26: 609–614.

    PubMed  PubMed Central  Google Scholar 

  29. Spink CF, Gray LC, Davies FE, Morgan GJ, Bidwell JL . Haplotypic structure across the I kappa B alpha gene (NFKBIA) and association with multiple myeloma. Cancer Lett 2007; 246: 92–99.

    CAS  PubMed  Google Scholar 

  30. Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin Proc 2007; 82: 1468–1473.

    PubMed  Google Scholar 

  31. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564–569.

    Article  PubMed  Google Scholar 

  32. Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood 2006; 107: 904–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY et al. Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood 2010; 116: 5501–5506.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Shoenfeld Y, Berliner S, Shaklai M, Gallant LA, Pinkhas J . Familial multiple myeloma. A review of thirty-seven families. Postgrad Med J 1982; 58: 12–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. McCrea AP, Morris TC . Concurrent familial myeloma in Northern Ireland. Cancer 1986; 58: 394–396.

    CAS  PubMed  Google Scholar 

  36. Roddie PH, Dang R, Parker AC . Multiple myeloma in three siblings. Clin Lab Haematol 1998; 20: 191–193.

    CAS  PubMed  Google Scholar 

  37. Lynch HT, Sanger WG, Pirruccello S, Quinn-Laquer B, Weisenburger DD . Familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst 2001; 93: 1479–1483.

    CAS  PubMed  Google Scholar 

  38. Gerkes EH, de Jong MM, Sijmons RH, Vellenga E . Familial multiple myeloma: report on two families and discussion of screening options. Hered Cancer Clin Pract 2007; 5: 72–78.

    PubMed  PubMed Central  Google Scholar 

  39. Grass S, Preuss KD, Thome S, Weisenburger DD, Witt V, Lynch J et al. Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM. Blood 2011; 118: 635–637.

    CAS  PubMed  Google Scholar 

  40. Ogawa M, Wurster DH, McIntyre OR . Multiple myeloma in one of a pair of monozygotic twins. Acta Haematol 1970; 44: 295–304.

    CAS  PubMed  Google Scholar 

  41. Judson IR, Wiltshaw E, Newland AC . Multiple myeloma in a pair of monozygotic twins: the first reported case. Br J Haematol 1985; 60: 551–554.

    CAS  PubMed  Google Scholar 

  42. Comotti B, Bassan R, Buzzetti M, Finazzi G, Barbui T . Multiple myeloma in a pair of twins. Br J Haematol 1987; 65: 123–124.

    CAS  PubMed  Google Scholar 

  43. Snowden JA, Greaves M . IgA lambda myeloma presenting concurrently in identical twins with subsequent transformation to 'aggressive phase' in one. Clin Lab Haematol 1995; 17: 95–96.

    CAS  PubMed  Google Scholar 

  44. Olujohungbe AB, Gledhill T, Satchithananathan G . Temporal development of myeloma in a syngeneic twin pair. Br J Haematol 2006; 133: 211–212.

    PubMed  Google Scholar 

  45. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78–85.

    CAS  PubMed  Google Scholar 

  46. Hemminki K . Re: familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst 2002; 94: 462–463, author reply 463.

    PubMed  Google Scholar 

  47. Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A et al. Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. Hum Mol Genet 2007; 16: 3117–3127.

    CAS  PubMed  Google Scholar 

  48. Pratt G, Fenton JA, Allsup D, Fegan C, Morgan GJ, Jackson G et al. A polymorphism in the 3' UTR of IRF4 linked to susceptibility and pathogenesis in chronic lymphocytic leukaemia and Hodgkin lymphoma has limited impact in multiple myeloma. Br J Haematol 2010; 150: 371–373.

    CAS  PubMed  Google Scholar 

  49. Morgan GJ, Adamson PJ, Mensah FK, Spink CF, Law GR, Keen LJ et al. Haplotypes in the tumour necrosis factor region and myeloma. Br J Haematol 2005; 129: 358–365.

    CAS  PubMed  Google Scholar 

  50. Roddam PL, Rollinson S, O'Driscoll M, Jeggo PA, Jack A, Morgan GJ . Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. J Med Genet 2002; 39: 900–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Davies FE, Rollinson SJ, Rawstron AC, Roman E, Richards S, Drayson M et al. High-producer haplotypes of tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment. J Clin Oncol 2000; 18: 2843–2851.

    CAS  PubMed  Google Scholar 

  52. Greenberg AJ, Rajkumar SV, Vachon CM . Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics. Blood 2012; 119: 5359–5366.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Vangsted A, Klausen TW, Vogel U . Genetic variations in multiple myeloma I: effect on risk of multiple myeloma. Eur J Haematol 2012; 88: 8–30.

    CAS  PubMed  Google Scholar 

  54. Vangsted A, Klausen TW, Vogel U . Genetic variations in multiple myeloma II: association with effect of treatment. Eur J Haematol 2012; 88: 93–117.

    CAS  PubMed  Google Scholar 

  55. Broderick P, Chubb D, Johnson DC, Weinhold N, Forsti A, Lloyd A et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet 2012; 44: 58–61.

    CAS  Google Scholar 

  56. Chubb D, Weinhold N, Broderick P, Chen B, Johnson DC, Försti A et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet 2013; 45: 1221–1225.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Goll MG, Bestor TH . Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005; 74: 481–514.

    CAS  PubMed  Google Scholar 

  58. Kangaspeska S, Stride B, Metivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP et al. Transient cyclical methylation of promoter DNA. Nature 2008; 452: 112–115.

    CAS  PubMed  Google Scholar 

  59. Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008; 452: 45–50.

    CAS  PubMed  Google Scholar 

  60. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE . G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 2008; 283: 32198–32208.

    CAS  PubMed  Google Scholar 

  61. Gamper CJ, Agoston AT, Nelson WG, Powell JD . Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol 2009; 183: 2267–2276.

    CAS  PubMed  Google Scholar 

  62. Brenner C, Deplus R, Didelot C, Loriot A, Vire E, De Smet C et al. Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J 2005; 24: 336–346.

    CAS  PubMed  Google Scholar 

  63. Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003; 102: 4504–4511.

    CAS  PubMed  Google Scholar 

  64. Walker BA, Leone PE, Jenner MW, Li C, Gonzalez D, Johnson DC et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood 2006; 108: 1733–1743.

    CAS  PubMed  Google Scholar 

  65. Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 2010 2010; 116: 2543–2553.

    CAS  PubMed  Google Scholar 

  66. Jones CH, Pepper C, Baird DM . Telomere dysfunction and its role in haematological cancer. Br J Haematol 2012; 156: 573–587.

    CAS  PubMed  Google Scholar 

  67. Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ et al. Common variants near TERC are associated with mean telomere length. Nat Genet 2010; 42: 197–199.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jones AM, Beggs AD, Carvajal-Carmona L, Farrington S, Tenesa A, Walker M et al. TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut 2012; 61: 248–254.

    CAS  PubMed  Google Scholar 

  69. Kote-Jarai Z, Olama AA, Giles GG, Severi G, Schleutker J, Weischer M et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 2011; 43: 785–791.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Houlston RS, Cheadle J, Dobbins SE, Tenesa A, Jones AM, Howarth K et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet 2010; 42: 973–977.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007; 11: 349–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Taddesse-Heath L, Meloni-Ehrig A, Scheerle J, Kelly JC, Jaffe ES . Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features. Mod Pathol 2010; 23: 991–999.

    PubMed  PubMed Central  Google Scholar 

  74. Dib A, Gabrea A, Glebov OK, Bergsagel PL, Kuehl WM . Characterization of MYC translocations in multiple myeloma cell lines. J Natl Cancer Inst Monogr 2008; 39: 25–31.

    CAS  Google Scholar 

  75. Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia 2011; 25: 1026–1035.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Jima DD, Zhang J, Jacobs C, Richards KL, Dunphy CH, Choi WW et al. Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs. Blood 2010; 116: e118–e127.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 2008; 105: 12885–12890.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 2010; 18: 367–381.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 2011; 147: 773–788.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Osman W, Okada Y, Kamatani Y, Kubo M, Matsuda K, Nakamura Y . Association of common variants in TNFRSF13B, TNFSF13, and ANXA3 with serum levels of non-albumin protein and immunoglobulin isotypes in Japanese. PLoS One 2012; 7: e32683.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kamatani Y, Matsuda K, Okada Y, Kubo M, Hosono N, Daigo Y et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 2010; 42: 210–215.

    CAS  PubMed  Google Scholar 

  82. Darce JR, Arendt BK, Wu X, Jelinek DF . Regulated expression of BAFF-binding receptors during human B cell differentiation. J Immunol 2007; 179: 7276–7286.

    CAS  PubMed  Google Scholar 

  83. Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103: 689–694.

    CAS  PubMed  Google Scholar 

  84. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Forzati F, Federico A, Pallante P, Fedele M, Fusco A . Tumor suppressor activity of CBX7 in lung carcinogenesis. Cell Cycle 2012; 11: 1888–1891.

    CAS  PubMed  Google Scholar 

  86. Zhang XW, Zhang L, Qin W, Yao XH, Zheng LZ, Liu X et al. Oncogenic role of the chromobox protein CBX7 in gastric cancer. J Exp Clin Cancer Res 2010; 29: 114.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Karamitopoulou E, Pallante P, Zlobec I, Tornillo L, Carafa V, Schaffner T et al. Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer. Eur J Cancer 2010; 46: 1438–1444.

    CAS  PubMed  Google Scholar 

  88. Scott CL, Gil J, Hernando E, Teruya-Feldstein J, Narita M, Martinez D et al. Role of the chromobox protein CBX7 in lymphomagenesis. Proc Natl Acad Sci USA 2007; 104: 5389–5394.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U et al. CBX7 is a tumor suppressor in mice and humans. J Clin Invest 2012; 122: 612–623.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gil J, Bernard D, Peters G . Role of polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol 2005; 24: 117–125.

    CAS  PubMed  Google Scholar 

  91. Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010; 38: 662–674.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Gil J, Bernard D, Martinez D, Beach D . Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 2004; 6: 67–72.

    CAS  PubMed  Google Scholar 

  93. Sawyer J . The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet 2011; 204: 3–12.

    PubMed  Google Scholar 

  94. Weinhold N, Johnson DC, Chubb D, Chen B, Forsti A, Hosking FJ et al. The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat Genet 2013; 45: 522–525.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F et al. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 2012; 474: 230–234.

    Google Scholar 

  96. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES . Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 2006; 25: 1620–1628.

    CAS  PubMed  Google Scholar 

  97. Chng WJ, Glebov O, Bergsagel PL, Kuehl WM . Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol 2007; 20: 571–596.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O et al. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res 2010; 70: 8802–8811.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Johnson DC, Ross FM, Dickens NJ, Davies FE, Child JA, Durie B et al. Association of Genetic Variants with FISH-Based Karyotyping Status in Multiple Myeloma Patients. Clin Lymphoma Myelom 2009; 9: S132–S133.

    Google Scholar 

  100. Pepe MS, Gu JW, Morris DE . The potential of genes and other markers to inform about risk. Cancer Epidemiol Biomarkers Prev 2010; 19: 655–665.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Morgan G, Johnsen HE, Goldschmidt H, Palumbo A, Cavo M, Sonneveld P et al. MAGIC (MyelomA Genetics International Consortium). Leuk Lymphoma 2011; 53: 796–800.

    Google Scholar 

  102. Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet 2010; 42: 661–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Enciso-Mora V, Broderick P, Ma Y, Jarrett RF, Hjalgrim H, Hemminki K et al. A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 2010; 42: 1126–1130.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M, Mansouri M et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet 42: 132–136.

  105. Asimit J, Zeggini E . Testing for rare variant associations in complex diseases. Genome Med 2011; 3: 24.

    PubMed Central  Google Scholar 

  106. Asimit J, Zeggini E . Rare variant association analysis methods for complex traits. Annu Rev Genet 2010; 44: 293–308.

    CAS  PubMed  Google Scholar 

  107. Morris AP, Zeggini E . An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol 2010; 34: 188–193.

    PubMed  Google Scholar 

Download references

Acknowledgements

Laboratory work of GJM is supported by funding from Myeloma UK. The work of RSH is supported by grants from Leukaemia Lymphoma Research and Myeloma UK. HG and KH are supported by funding was provided to Dietmar-Hopp-Stiftung in Walldorf, The German Ministry of Education and Science (Gliomics 01ZX1309B), the German Cancer Aid, Deursche Krebshilfe and the University Hospital Heidelberg.

Author information

Authors and Affiliations

  1. Division of Molecular Pathology, Haemato-Oncology Research Unit, Institute of Cancer Research, Surrey, UK

    G J Morgan & D C Johnson

  2. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    N Weinhold & H Goldschmidt

  3. Multiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    O Landgren

  4. Department of Preventive Medicine, Creighton's Hereditary Cancer Center, Omaha, NE, USA

    H T Lynch

  5. Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany

    K Hemminki

  6. Center for Primary Health Care Research, Lund University, Malmö, Sweden

    K Hemminki

  7. Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK

    R S Houlston

Authors
  1. G J Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D C Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Weinhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O Landgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H T Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Hemminki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R S Houlston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G J Morgan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morgan, G., Johnson, D., Weinhold, N. et al. Inherited genetic susceptibility to multiple myeloma. Leukemia 28, 518–524 (2014). https://doi.org/10.1038/leu.2013.344

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.344

Keywords

This article is cited by

Search

Advanced search

Quick links