Haematologica 2003 - Supplements

lead to the identification of recurrent chromosome
rearrangements which are specific for the disease and in some
instances of clinical and biologic significance. It is now well
established that up to 50% of the MM cases show rearrangements
involving the IGH locus at 14q32. This proportion might be even
higher if rearrangements of the IG lambda (IGL) locus at 22q11.2
are included. Three specific translocations involving the IGH
locus at 14q32, i.e. t(4;14), t(11;14) and t(14;16), account for
nearly half of the 14q32 translocations in MM. The remaining
IGH and IGL translocations are obviously of much lower
frequency but nevertheless recurrent, like t(6;14), t(14;20) or
t(8;22). Nowadays, two groups of cases are of major interest for
the identification of genetic markers in MM: those with
immunoglobulin breakpoints involving novel partner genes and
those with recurrent breakpoints not involving IG. .
We have selected from our files 12 cases of de novo MM with
complex karyotype which by G-banding lacked the most common
translocations t(4;14), t(11;14), and t(14;16). These cases were
analysed by SKY as well as by FISH using probes flanking the
IGH and IGL genes.
IGH breakpoints at 14q32: Four cases that showed 14q32
rearrangement were re-classified by SKY as t(11;14)(q13;q32) (3
cases) and as t(14;20)(q32;q13.1) (1 case). FISH analysis
detected the involvement of the MAFB gene in the latter case.
IGL breakpoints at 22q11.2: Eight cases showed a rearrangement
at 22q11.2 by SKY. FISH analyses detected involvement of the
IGL locus in four of these cases. All four cases showed the
t(8;22)(q24;q11.2) variant Burkitt translocation. These
translocations were always balanced.
Non-IGL-breakpoints at 22q11.2: The remaining four MM lacked
evidence for IGL involvement by FISH. An unbalanced
translocation der(1)t(1;22)(p13;q11.2) was present in two cases.
In addition, two other translocations with a non-IGL breakpoint
in 22q11.2 were noted: a t(10;22)(q?;q11.2) and a
t(11;22)(p11.2;q11.2), each one being present in one case.
Other new recurrent non IG-breakpoints: The most frequent
breakpoint location was in band 1p13 (9/12 cases). Except for the
two cases with the recurrent translocation t(1;22) and two cases
with deletions the 1p13 breakpoints were due to non-recurrent
rearrangements. Breakpoints at 13q14-q21, Xp11.2, and Xq21
were detected in each three MM but different partners were
involved.
The described cytogenetic findings warrant further molecular
evaluation but clearly provide evidence for the existence of genes
yet to be discovered that play an important role in the
pathogenesis of MM.
041
In multiple myeloma, five common genomic aberrations
(+1q, +9q, +11q, 13q-, t14q) display a non-random
distribution and suggest novel pathogenetic pathways
P. Liebisch, D. Scheck, S. Erné, A. Wellmann, C. Straka, H.
Einsele, H. Goldschmidt, A. Benner, S. Stilgenbauer,
H. Döhner
Dept. of Internal Medicine III, University Hospital of Ulm, Ulm,
Germany Med. Klinik - Innenstadt, Ludwig-Maximilians-Universität,
München, Germany Dept. of Internal Medicine II, University
Hospital of Tübingen, Tübingen, Germany Med. Klinik und
Poliklinik V, University Hospital of Heidelberg, Heidelberg,
Germany Central Unit Biostatistics, German Cancer Research
Center (DKFZ), Heidelberg, Germany
Introduction and Aims: Genomic aberrations play a key role in
the pathogenesis of multiple myeloma (MM) and provide crucial
prognostic information in this disease. Translocations involving
the immunoglobulin heavy chain (IgH) locus on chromosome
14q32 (t14q) lead to the dysregulation of various oncogenes and
are early genetic rearrangements in the development of plasma
cell tumors. Deletion of chromosome arm 13q (13q-) is a
powerful and independent predictor of an unfavorable outcome in
MM. The biological implications and the prognostic significance
of other recurring chromosomal losses and gains are unknown.
Using FISH and a comprehensive, disease-specific DNA probe
set, a high incidence of chromosome 1q, 9q, and 11q trisomies
(+1q, +9q, +11q) were recently demonstrated in a large
prospective series of myeloma tumors. To determine the
significance of these frequent chromosomal gains, we evaluated
the incidences of 13q- and t14q depending on the presence or
absence of +1q, +9q, and +11q .
Material and Methods: Bone marrow aspirates from 182 patients
with MM were obtained during routine diagnostic procedures.
The following DNA probes were used for tri-color FISH: RP11-
71L20 (mapping to chromosome band 1q21), RP11-40A07
(9q34), RP11-17M17 (11q25 – all from the RPCI human BAC
library 11, National Center for Biotechnology Information,
NCBI; http://www.ncbi.nlm.nih.gov/), PAC clone 272/3 (13q14,
locus D13S272), and two DNA clones covering the IgH constant
and variable region (BAC CH and cosmid VH). According to
published data, t14q was diagnosed in tumors that exhibited
segregating CH/VH signals in >25% of plasma cells.
Results: In a series of 182 cases, 13q- was significantly less
common in tumors with +11q or +9q compared to those lacking
these gains (31% vs. 70% and 39% vs. 65%, respectively; p