Genetics of multiple myeloma: another heterogeneity level?

Abstract

Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.

Figure 1

B-cell differentiation. The first step of B-cell engagement is characterized by an IGH DH-JH rearrangement, followed by a VH-DH-JH fusion. If “productive” (or successful), these IGH rearrangements are followed by recombinations of the IGLκ, and/or IGLλ genes. These DNA rearrangements take place within the bone marrow and are totally antigen independent. The B cells then migrate to the secondary lymphoid organs where, within the germinal centers, they terminate their differentiation through the SMH and CSR processes. This differentiation step is antigen dependent, in cooperation with dendritic and T cells. The oncogenetic event is supposed to take place after this long differentiation process, before the migration of the plasma cell to bone marrow.

Figure 2

Oncogenetic model. Quickly after the oncogenetic event(s), differential mutations occur, creating subclones. The 2 main oncogenetic pathways are the “trisomy” pathway and the 14q32 translocation pathway. Secondary events occur later during evolution.

Figure 3

Subclonal evolution. Two different types of subclonal evolution can be observed: a “linear” evolution with accumulation of genetic events (A) and a “branching” evolution with early divergence of subclones with different mutations, which are differentially selected during evolution (B).

Figure 4

MM subentities defined by SNP array. In this picture of 192 patients with MM at diagnosis, several subgroups can be identified: monosomies 13 and 14 and frequent 1p deletions (1); monosomies 13 and 1q gains (2); hyperdiploidy (3); and within hyperdiploidy, patients with monosomies 13 and lack of trisomy 11 (4). Adapted from Avet-Loiseau et al with permission.