Genetic events in the pathogenesis of multiple myeloma - PubMed (original) (raw)

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Genetic events in the pathogenesis of multiple myeloma

W J Chng et al. Best Pract Res Clin Haematol. 2007 Dec.

Abstract

The genetics of myeloma has been increasingly elucidated in recent years. Recurrent genetic events, and also biologically distinct and clinically relevant genetic subtypes of myeloma have been defined. This has facilitated our understanding of the molecular pathogenesis of the disease. In addition, some genetic abnormalities have proved to be highly reproducible prognostic factors. With the expanding therapeutic armamentarium, it is time to include genetic assessment as part of clinical evaluation of myeloma patients to guide management. In this review we examine the role of various genetic abnormalities in the molecular pathogenesis of myeloma, and the use of such abnormalities in disease classification, prognosis and clinical management.

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Figures

Figure 1

Figure 1

Disease stages and timing of oncogenic events (see text for further details). The degree of intersection between the overlapping triangles estimates the percentage of each genetic subgroup with coexisting genetic abnormalities. The translocation partners in the IgH translocation (TLC) group are ordered according to increasing frequency of concurrent Δ13. The different mutations activating the different signaling or cell-cycle regulatory pathways are mutually exclusive, i.e., RAS and FGFR3 mutations always occur in different patients. *The 8q24 partner referred to here is MAFA; C-MYC is also located on 8q24, but these are usually secondary IgH TLCs.

Figure 2

Figure 2

The t(4;14) translocation further dissects the survival of high-risk patients defined by 17-gene high-risk molecular signature. Combination of t(4;14) and high risk defined by the 17-gene model (logQ4/Q1 > 0.85) identifies three groups of patients with significantly different survival (log-rank P < 0.0001) in patients entered into total therapy II (n = 351): a high-risk group (n = 16), defined by presence of logQ4/Q1 > 0.85 and t(4;14), with a median overall survival of 16.7 months; an intermediate-risk group (n = 45), defined by the presence of logQ4/Q1 > 0.85 without t(4;14), with a median overall survival of 39.8 months; and a low-risk group (n = 289), defined by logQ4/Q1 < 0.85, with a median survival not yet reached. (Gene expression and survival data available from the NCBI Gene Expression Omnibus [GEO] using accession number GSE2658.) For patients with logQ4/Q1 < 0.85, the presence of t(4;14) did not significantly alter survival and is therefore combined for survival analysis.

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