Abstracts of 4th Annual UKMF Scientific Meeting on 07-Feb-2003
Molecular cytogenetic classification of multiple myeloma: clinical implications
Herve Avet-Loiseau, Laboratoire d'Hematologie, Institut de Biologie, Nantes, France
Cytogenetic analyses in multiple myeloma (MM) are characterized by a high incidence of normal karyotypes (in about 2/3 of the patients). However, studies based on DNA index measurement or interphase fluorescence in situ hybridisation (FISH) have revealed an aneuploidy in at least 90% of the patients. This discrepancy is related to the low proliferative index of plasma cells, normal karyotypes corresponding to normal myeloid bone marrow cells. In order to circumvent this pitfall, many authors have developed interphase FISH strategies, enabling analysis of chromosomal abnormalities independently of the proliferative status. In contrast to most other B-cell malignancies, MM displays extensive chromosomal abnormalities involving virtually every chromosome. However, several recurrent abnormalities (numerical and structural) have been described, and especially hyperdiploidy (involving odd chromosomes), translocations involving the 14q32 band [t(14q32)], and chromosome 13 deletions/monosomies [del(13)].
Del(13) are observed in 40% to 50% of the patients, and mostly involve the whole chromosome 13 (monosomy in 90% of the cases), preventing the definition of a minimal deleted region containing a putative tumour suppressor gene. Since the pioneer study published by Barlogie's group, many studies have confirmed the prognostic value of del(13). However, controversies still persist regarding the method of del(13) detection. Whereas interphase FISH detects del(13) in 40% to 50% of the patients, conventional cytogenetics enables its identification in only 15% of them. However, it seems that the detection of del(13) by cytogenetics confers a poorer prognosis than its detection by interphase FISH only.
T(14q32) are observed in 60% to 70% of the patients. Despite a high variability in the chromosomal partners (more than 30 different chromosomal bands have been reported), two translocations are more frequent, i.e., the t(4;14)(p16;q32) and the t(11;14)(q13;q32), observed in about 15% of the patients each. Cloning of the translocation breakpoints have revealed that the t(11;14) deregulates the gene encoding cyclin D1. The situation is probably more complex for the t(4;14), which appears to deregulate two genes: FGFR3 and MMSET. Recent reports have shown that these two translocations have opposite prognostic implications. Whereas the t(4;14) confers a poor prognosis, the t(11;14) seems to be associated with a long survival, especially in patients receiving high dose therapy.
Finally, ploidy defines two groups of patients: those with hyperdiploidy (about 60% of the patients), and those with hypo/pseudodiploidy. This latter group seems to associated with a poor prognosis, independently of the chromosome 13 status. In contrast, hyperdiploidy is associated with a good prognosis only in the absence of concomitant del(13).
In conclusion, cytogenetics has become a major prognostic indicator enabling a stratification of patients enrolled in prospective therapeutic trials. However, the analysis of chromosomal abnormalities raises the question of the optimal technique used for their identification.