Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics

To delineate multiple myeloma (MM) subgroups and their clonal evolution, we analyzed 81 newly diagnosed patients by interphase fluorescence in situ hybridization using a comprehensive probe set for 10 chromosomes and two IGH rearrangements. A median of 5 probes per patient displayed aberrant signal numbers (range, 1-10). Additional copies most frequently found were for 15q22, 19q13, 9q34, 11q23, and 1q21. Losses commonly observed were of 13q 14.3, 17p 13, and 22q 11. Predominance of gain or loss was quantified by a copy number score (CS) for each patient. Two peaks (CS = +3 and CS = 0) were found by plotting patient copy number scores over CS values corresponding to hyperdiploid and nonhyperdiploid MM. Cluster analysis revealed four major branches: (i) gain of 9q, 15q, 19q, and/or 11q; (ii) deletion of 13q and t(4; 14); (iii) t(11; 14); and (iv) gain of 1q. Statistical modeling of an oncogenetic tree indicated that early independent events were gain of 15q/9q and/or 11q, t(11; 14); deletion of 13q followed by t(4; 14); and gain of 1q. Aberrations of 17p13, 22q11, 8p12, and 6q21 were found as subsequent events. MM with gain of I q was delineated as a subentity with significantly higher beta-2-microglobulin and lower hemoglobin levels, indicating a poor prognosis. From our results, we propose a model of MM for clonal evolution. (c) 2005 Wiley-Liss, Inc.