Monosomy 13 Is Associated With the Transition of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Abstract

Chromosomal abnormalities are present in most (if not all) patients with multiple myeloma (MM) and primary plasma cell leukemia (PCL). Furthermore, recent data have shown that numerical chromosomal changes are present in most individuals with monoclonal gammopathy of undetermined significance (MGUS). Epidemiological studies have shown that up to one third of MM may emerge from pre-existing MGUS. To clarify further possible stepwise chromosomal aberrations on a pathway between MGUS and MM, we have analyzed 158 patients with either MM or primary PCL and 19 individuals with MGUS using fluorescence in situ hybridization (FISH). Our FISH analyses were designed to detect illegitimate IGH rearrangements at 14q32 or monosomy 13. Whereas translocations involving the 14q32 region were observed with a similar incidence (60%) in both conditions, a significant difference was found in the incidence of monosomy 13 in MGUS versus MM or primary PCL. It was present in 40% of MM/PCL patients, but in only 4 of 19 MGUS individuals. Moreover, whereas monosomy 13 was found in the majority of plasma cells in MM, it was observed only in cell subpopulations in MGUS. It is noteworthy that, in a group of 20 patients with MM and a previous MGUS history, incidence of monosomy 13 was 70% versus 31% in MM patients without a known history of MGUS (P = .002). Thus, this study highlights monosomy 13 as correlated with the transformation of MGUS to overt MM and may define 2 groups of MM with possible different natural history and outcome, ie, post-MGUS MM with a very high incidence of monosomy 13 and de novo MM in which other genetic events might be involved. Serial analyses of individuals with MGUS will be needed to validate this model.

Chromosomal and genetic abnormalities in myeloma

“…The c‐ myc on chr 8q24 is the oncogene characteristically dysregulated in murine plasmacytoma and human Burkitt's lymphoma. Reciprocal translocations involving chromosome 8q24 and the Ig genes account for only 25% of the c‐ myc rearrangements in MM (Avet‐Loiseau et al ., 2001b), with the majority involving non‐Ig loci. Hence c‐ myc rearrangements will be discussed below with the non‐Ig translocations (see Section IIIB).…”

Cytogenetic patterns in multiple myeloma after a phase of preceding MGUS

“…The second abnormality deserving attention in the setting of MM post-MGUS is del(13q14). In MGUS, the French group reported on a lower incidence of a del(13q14) as compared with MM [32]. This observation would imply that del(13q14) may be involved in the progression from MGUS to MM.…”

Prognostic impact of cytogenetic aberrations in patients with multiple myeloma or monoclonal gammopathy of unknown significance

“…5-45% of MGUS-patients show a deletion in 13q14 [52,54,55]. Upto now contradictory data exist whether this aberration leads to an earlier progression into multiple myeloma or not [55][56][57]. Also the association between the deletion of the long arm of chromosome 13 and the t(4;14) and its meaning regarding course of the disease remains unclear [58].…”