Haematologica 2003 - Supplements
Haematologica 2003 - Supplements
Haematologica 2003 - Supplements
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2. Genetic heterogeneity in MM: impact<br />
on diagnosis and therapy<br />
2.1 IGH rearrangement<br />
021<br />
Low frequency of IgH rearrangement in UK plasma cell<br />
dyscrasias.<br />
Fiona M Ross, Ashraf H Ibrahim, Amy Jones, Rebecca KM<br />
Protheroe, Mark O Winfield, Jude BL Gunasekera,<br />
Christopher S Wragg, Armelle Vilain-Holmes<br />
LRF UK Myeloma Forum Cytogenetics Database, Wessex<br />
Regional Genetics Laboratory, Salisbury, UK, and Human<br />
Genetics Division, University of Southampton, Southampton, UK.<br />
Interphase FISH has been carried out on CD138-purified plasma<br />
cells from 251 cases of plasma cell dyscrasia (2 PCL, 219 MM,<br />
27 MGUS, 3 primary amyloidosis) from 32 UK centres. 75%<br />
cases were studied at diagnosis. 95% were abnormal when tested<br />
for IgH rearrangement, 13q14 loss, p53 loss, or numbers of<br />
centromeres of chromosomes 3, 6, 7, 9, 10, 11 and 17. Clear<br />
associations between these abnormalities were observed.<br />
Only 43% overall showed an IgH translocation (44% MM, 100%<br />
PCL, 26% MGUS, 66% PA), much less than expected from the<br />
literature. However, the overall rates of t(11;14) (16%), t(4;14)<br />
(7%) and t(14;16) (3%) were not significantly different from<br />
expected. Part of the explanation for the low IgH abnormality rate<br />
may have been due to a higher proportion of older patients in our<br />
series, as we saw a clear trend towards decreasing IgH<br />
rearrangement with increasing age (53% in the 40s to 32% aged<br />
80+).<br />
IgH rearrangement was slightly increased in IgA cases (53%)<br />
relative to IgG cases (37%) and t(4;14) was significantly overrepresented<br />
in IgA cases (18%) vs 3% in IgG cases. The t(11;14)<br />
was seen in 2/3 non-secretory MM. MGUS cases did not show<br />
t(4;14) or t(14;16). 29% of t(4;14) cases had lost the signal for the<br />
derived 14 in a high proportion of cells, confirming that the<br />
FGFR3/IgH fusion is less important in maintenance of myeloma<br />
than the MMSET/IgH fusion on the der(4).<br />
37% cases overall showed deletion of Rb and/or D13S319 from<br />
chromosome 13. The rate was higher in MM than MGUS (40%<br />
vs 15%). The 6 cases of MM known to have had a preceding<br />
MGUS had a 66% del(13) rate lending support to the theory that<br />
acquisition of del(13) may be involved with the development of<br />
MM from MGUS.<br />
64% cases appeared to be substantially hyperdiploid. As<br />
expected, these had a lower frequency of del(13) (25%) than<br />
those cases that were probably pseudodiploid or hypodiploid<br />
(51%). 88% of cases with no visible numerical abnormalities<br />
(counting del(13) as a numerical change) had t(11;14). The<br />
t(11;14) was rarely associated with del(13) (18%) or<br />
hyperdiploidy (15%). The t(4;14) and t(14;16) cases showed<br />
del(13) in 76% and 71% respectively. However, conventional<br />
cytogenetic results available for 3 of these cases with apparently<br />
normal 13s indicated that loss of 13 relative to a near-triploid or<br />
near-tetraploid karyotype had been masked. The t(4;14) cases<br />
also showed a reduced rate of significant hyperdiploidy (18%)<br />
but had evidence of many more abnormalities of single<br />
chromosomes than t(11;14) cases.<br />
Only 8 cases (3%) had significant deletion of p53. However 78%<br />
of 14 cases with an additional 17 centromere did not show an<br />
extra p53. It is unclear whether this relative loss of p53 is<br />
significant.<br />
Only one of 50 cases tested for ATM deletion was abnormal<br />
indicating this is not an important cause of chromosome<br />
instability in myeloma.<br />
Thus FISH studies are continuing to demonstrate and refine<br />
patterns of chromosome abnormalities and their association with<br />
other features of myeloma.<br />
022<br />
14q32 translocations in multiple myeloma patients<br />
Christian Bastard, Dominique Leroux, Jean Soulier, Sylvie<br />
Dumont, Catherine Arnould, Sylvie Taviaux, Jean Louis<br />
Taillemite1, Nicole Véronique Smadja.<br />
centre Henri Becquerel, Rouen, CHU Grenoble, Hopital Saint<br />
Louis, Paris, Hopital Saint Antoine, Paris, France<br />
Translocations involving the immunoglobulin heavy chain (IgH)<br />
genes are frequent in multiple myeloma (MM) patients. Using<br />
conventional cytogenetics, MM can be separated into two groups<br />
according to the chromosome number pattern, and 14q32<br />
translocations are more frequently associated with hypodiploid<br />
than with hyperdiploid karyotypes (Smadja et al, Blood, 2001 :<br />
total IgH rearrangements 31%, hyperdiploid group 11%,<br />
hypodiploid group 56%). However, conventional cytogenetics<br />
misses cryptic translocations, especially t(4;14)(p16;q32).<br />
Furthermore, recent interphase fluorescent in situ hybridization<br />
(FISH) studies found 14q32 translocations in as much as 75%<br />
MM patients. In order to identify in which CC group we failed to<br />
detect these translocations, we design a study using FISH with a<br />
dual color break appart IgH probe on previously R-banded<br />
metaphases, allowing to detect both 14q32 translocations and<br />
overall chromosomal abnormalities in a new series of 55 patients<br />
with abnormal karyotypes. Upon conventional cytogenetics<br />
analysis, 2/29 hyperdiploid (7%) and 9/26 hypodiploid patients<br />
(35%) had a 14q32 translocation. Using the FISH assay, twelve<br />
t(4;14) were identified, in 2 hyperdiploid (7%) and 10<br />
hypodiploid (38.5%) cases, respectively. This abnormality was<br />
always associated with a chromosome 13 monosomy. We<br />
therefore confirm that 14q32 translocations are much more<br />
frequent in hypodiploid (73.5%) than in hyperdiploid patients<br />
(14%), (p< .0001), and that cryptic t(4;14)(p16;q32) is strongly<br />
associated with hypodiploid karyotypes (p< .01). This study also<br />
confirms the heterogeneity of the hypodiploid group, in which<br />
several subgroups can be recognized depending on IgH genes<br />
translocations. Using this reliable assay, only 42% of patients had<br />
a 14q32 translocation.<br />
023<br />
Detection of chromosomal breakpoints affecting the<br />
IGH, IGL and IGK loci by interphase FISH in MM and<br />
MGUS with normal karyotype.<br />
Borja Saez, José I. Martín-Subero, María D. Odero, Juan<br />
C. Cigudosa, Roberto Hernández, Marta Pérez-Salazar,<br />
Felipe Prosper, Reiner Siebert, María J. Calasanz<br />
1. Department of Genetics, University of Navarra, Pamplona, Spain<br />
2. Institute of Human Genetics, University Hospital Schleswig-<br />
Holstein, Campus Kiel, Germany 3. Department of Human<br />
Genetics, Spanish National Cancer Center, Madrid, Spain 4.<br />
Department of Hematology, Hospital Txagorritxu, Vitoria, Spain 5.<br />
Department of Hematology, Clínica Universitaria, Pamplona, Spain<br />
The routine application of conventional cytogenetic techniques<br />
for the diagnosis of plasma cell disorders (PCD) is often<br />
unsuccessful. The percentage of patients with non-informative<br />
karyotypes is around 60-70% in multiple myeloma (MM) and<br />
S97