Genetic analyses of multiple myeloma and related plasma cell dyscrasias

Sammanfattning: Acquired genetic changes have proved to be of diagnostic and prognostic importance in different hematologic malignancies as well as in some solid tumor types. However, although multiple myeloma (MM), an incurable disease, and its proceeding stage monoclonal gammopathy of undetermined significance (MGUS) are quite common, little is known about the karyotypic features of these plasma cell dyscrasias. One reason for this is that a large proportion of the cases are karyotypically normal, despite the fact that molecular genetic studies have revealed that virtually all MM and most MGUS harbor cytogenetic aberrations. Thus, the non-neoplastic cells seem to have a proliferative advantage in vitro. The goals of the present thesis were to develop different culture methods and to identify and characterize chromosomal abnormalities in MGUS/MM. A total of 279 cell cultures were investigated as part of this thesis, and various culture conditions were evaluated in articles I, IV, and V. Chromosomal anomalies were identified in 46-63% of the MM/MGUS/smoldering multiple myeloma (SMM) cases by conventional cytogenetics and the majority were aberrant when performing both cytogenetics and fluorescence in situ hybridization. There was no evidence that gender, age, disease phase, culture time, plasma cell percentage, or cytokine stimulation significantly influenced the karyotypic features. In article II, cytogenetic features in 783 cytogenetically abnormal MM cases were ascertained. Hyperdiploidy was the most common modal number and about 3/4 of the MM karyotypes were complex, with a median of eight changes per patient. The most frequent genomic breakpoints and imbalances were 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 19q13, 1p22, 6q21, 17p11, and +9, -13, +15, +19, +11, and -Y. Hyperdiploidy was more common in elderly patients, trisomy 11 and monosomy 15 were more common among men, while -X was more frequent in women. Loss of chromosome Y, as the sole change, and +5 were more common in elderly patients, and -14 was more frequent in the younger age group. The salient results of article III were that cytogenetic features generally can be used to distinguish between MM and myelodysplastic syndromes/ acute myeloid leukemia arising after previous chemotherapy (t-MDS/t-AML) for MM, that del(20q) as a sole change is found in approximately 10% of MM/MGUS, that the presence of 20q- in MM/MGUS/SMM not by necessity implies emerging MDS/AML, that it frequently arises de novo, i.e. in untreated MM/MGUS/SMM patients, and that del(20q) is present in myeloid and lymphoid cells as well as in progenitor/stem cells, at least in the MGUS case investigated.