Table 1.

Controversial issues in genetics of MM

Assumption	Controversy	Hypothesis/question/exploration
The t(4;14) largely involves the switch regions, suggesting errors during the CSR process.	Some of the IGH translocations may take place not in secondary lymphoid organs but within the bone marrow during the maturation IGH rearrangements	Occurrence of RAG-mediated molecular errors during a (re-)edition of the B-cell receptor.
The oncogenic transformation in MM is thought to occur within secondary lymphoid organs.	More than 4% of patients have 2 unrelated clones with different VDJ rearrangements.	Possibility of evolution of 2 independent clones at an earlier stage of plasma cells before VDJ rearrangement.
Hyperdiploidy is probably because of missegregation of chromosomes during mitosis.	The nature of the gained chromosomes in hyperdiploidy is totally different between ALL and MM.	Do chromosomes have a specific disposition on the mitotic plaque in MM as compared with ALL, leading to gains of different chromosomes?
Some of the 14q32 translocations are recurrent.	The selectivity in the nature of 14q32 translocation partners is not fully understood.	The vicinity of chromosomal domains of chromosomes 14, 11, and 4 at certain times of SMH or CSR.
Several subclones coexisting at the same time in a single patient are similarly distributed in all locations.	Several subclones coexisting at the same time in a single patient have differential locations.	Several aspirates/biopsies should be performed in a single patient, ideally MRI- or PET-CT-guided on focal lesions, with subsequent evaluation for clonal content and subclone distribution
The subclone selection is under therapeutic pressure.	The subclone selection occurs in the natural history of the disease, which includes growth potential of the subclones or their interaction with their microenvironment.	Data supporting both hypotheses. The only way to answer this question would be to systematically analyze the diagnostic and first relapse specimens in a homogeneously treated cohort of patients.
Rare recurrent mutations observed only in subclones include genes supposed to act as drivers, such as NRAS, KRAS, and BRAF.	Driver mutations are not always expressed at the RNA level.	Need for future analyses at the protein level and to define the role of some of the known DNA repair mechanisms in inducing clonal change.

ALL, acute lymphoblastic leukemia; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.