Molecular Genetics of Multiple Myeloma

Abstract

Multiple myeloma (MM) is the second most common haematologic malignancy causing significant mortality and morbidity. The initial malignant clone undergoes multistep transformation, which could results from genetic and epigenetic deregulation, the acquisition of clonogenic properties and also abnormal interaction with tumour microenvironment. Two patterns of primary genetic events have been described: recurrent translocations involving the immunoglobulin heavy chain (IgH) locus and hyperdiploid characterised by chromosomal trisomies. Besides playing an important role in disease pathogenesis, these genetic abnormalities also have important prognostic impact. Further, the genes and pathways dysregulated in high‐risk disease can be used to develop specific therapeutic strategies. In this article, we concentrate on molecular pathways deregulated by genetic and epigenetic abnormalities, and their potential biological and clinical implications.

Key Concepts:

  • All multiple myeloma have a preceeding premalignant monoclonal gammopathy of undetermined significance phase.

  • Two dichotomous pathways are involved in disease initiation: translocations involving the immunoglobulin heavy chain and hyperdiploidy involving recurrent trisomies in chromosomes 3, 5, 7, 9, 11, 15 and 19.

  • All primary disease‐causing events lead to universal overexpression of one or more cyclin D gene.

  • MYC activation or reduction of retinoblastoma gene functions may be involved in disease transformation.

  • Additional mutations affecting the nuclear factor kappaB and p53 pathways may lead to independence from stromal environment leading to disease progression.

  • Genetic abnormalities are powerful prognostic factors in myeloma and can be used to define patients with high‐risk disease.

  • Certain novel therapeutic agents can overcome the poor prognosis of cytogenetics. As such, risk stratification in the treatment of myeloma is a possibility.

Keywords: myeloma; cytogenetics; fluorescence in situ hybridisation; microRNA; epigenetics; translocations; prognosis; nuclear factor kappaB; cyclin D; P53 pathways

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Further Reading

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San‐Miguel J, Harousseau JL, Joshua D and Anderson KC (2008) Individualizing treatment of patients with myeloma in the era of novel agents. Journal of Clinical Oncology 26: 2761–2766.

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Bi, CL, and Chng, WJ(Sep 2010) Molecular Genetics of Multiple Myeloma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022446]