Illegitimate switch recombinations are present in approximately half of primary myeloma tumors, but do not relate to known prognostic indicators or survival

The myeloma plasma cell is a postgerminal center, isotype-switched B cell, Chromosomal translocations into immunoglobulin heavy chain (IgH) switch reg ions, recombination sites in isotype switching, were initially demonstrated in myeloma cell lines but only a limited number of primary tumors. Molecul ar cytogenetics have since been applied to a series of primary tumors, in w hich IgH translocations accounted for many recurrent aberrations, among num erous nonrecurrent changes of unknown significance. This study, therefore, examined primary myeloma for IgH switch translocations using an established Southern blot assay that detected illegitimate switch recombinations, Sens itivity of the method was established by confining the analysis to 21 sampl es (4 stable, 17 progressive disease) with demonstrable legitimate isotype switches, of a total of 60 samples. illegitimate recombinations were found in 12 or 57% (1 stable, 11 progressive) of 21 samples, comparable with esti mates by molecular cytogenetics, The presence of switch translocations was supported by demonstrating up-regulated expression in myeloma marrow of cyc lin D1 and fibroblast growth factor receptor 3 (FGFR3), candidate oncogenes on chromosomes 11q13 and 4p16, respectively. Illegitimate switches were de tected most frequently in S mu, with more than one region involved in 6 cas es. Although these results confirmed the presence of switch translocations in primary myeloma, their absence in 43% of cases may imply heterogeneity o f pathogenesis, In progressive disease, there was no significant difference between patients with and without illegitimate switches in survival, nor t he prognostic indicators of beta (2) microglobulin (beta (2)m) and serum th ymidine kinase (STK). Hence IgH switch translocations as a single entity ar e unlikely to be a feature of disease progression or have prognostic signif icance, (C) 2001 by The American Society of Hematology.