2008 Barcelona - European Society of Human Genetics

Cancer genetics
preparations were obtained by GTG banding of blood and bone marrow
cells . On presentation 30% of cases revealed 46, XX and 46, XY
normal karyotypes and 70% of cases revealed abnormal karyotypes
del(5q),-7,del(6q),del (11q) .Out of 20 cases 1 case revealed an addition
of chromosome 9, 47,XX+9(90%) and 46,XX(10%) metaphase .
Trisomy 9 is a rare chromosomal aberration found in MDS, to the best
of our knowledge this is the first published report of trisomy 9 as a sole
chromosomal aberration in MDS . The presence of trisomy 9 in such
cases carries a poor prognosis and thus cytogenetic studies help to
correlate the genotype with the phenotype .
P04.108
Complex cytogenetic findings in bone marrow of an elderly
patient with chronic idiopathic myelofibrosis
T. Bulakbasi 1 , M. K. Yuksel 2 , Z. Yilmaz 1 , F. I. Sahin 1 ;
1 Baskent University Faculty of Medicine Department of Medical Genetics, Ankara,
Turkey, 2 Dr. Abdurrahman Yurtarslan Oncology Training and Research
Hospital, Ankara, Turkey.
Chronic idiopathic myelofibrosis is a chronic myeloproliferative disorder
characterized by splenomegaly, myeloid metaplasia and reactive
bone marrow fibrosis. Clonal cytogenetic abnormalities are observed
in 30 to 75% of the patients . Among these, trisomy 1q, 20q-, 13q- and
+8 are the most common aberrations . Here we report a 70-year-old
male patient with massive splenomegaly . His leukocyte count was
2300/mm 3 , hemoglobin 6,5 mg/dl and thrombocyte count 700 000/mm 3
on admission . Bone marrow biopsy revealed signs of chronic myeloproliferative
changes and dysmegakaryopoiesis and no specific diagnosis
was established. During disease classification studies, he received
hydroxyurea treatment, splenic radiotherapy and multiple blood
transfusions . The clinical course worsened in the following months and
the second bone marrow biopsy revealed myelofibrosis. Cytogenetic
analysis of the bone marrow sample revealed a karyotype reported
as 46,XY,del(9)(q22q34),t(8;17;21)(q22;q21;q22)[23]/46,XY[2], with a
previously undefined three-way translocation and a deletion in chromosome
9 . The patient died shortly thereafter . Karyotype analysis of
the bone marrow is an integral part of diagnosis in myeloproliferative
disorders, especially as a discriminative tool in ruling out reactive conditions
.
P04.109
inducible expression of the oncogenic transcription factor EVI
in human myeloid cells leads to phenotypes characteristic of
myelodysplastic syndromes (mDs)
T. Konrad, R. Wieser;
Medical University of Vienna, Vienna, Austria.
The EVI1 gene, which codes for a zinc finger transcription factor, is
overexpressed in subsets of patients with acute myeloid leukemia
(AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes
(MDS) . Its overexpression in AML has been studied intensively
because it is associated with particularly aggressive disease . However,
recent bone marrow transduction/transplantation studies in mice have
shown that EVI1 overexpression by itself causes MDS, while AML arises
only in the presence of additional, cooperating genetic events .
To gain a better understanding of the biological properties of EVI1, an
HA-tagged version of the human EVI1 cDNA was expressed in human
U937 myelomonocytic cells in a tetracycline regulable manner . Induction
of EVI1 in this system strongly inhibited cellular multiplication, an
effect that was in part due to cell cycle arrest, and in part to increased
rates of apoptosis . Exposure of EVI1 expressing cells to differentiation
stimuli caused cells to die rather than to differentiate . The c-myc
gene, which is implicated in the control of cellular proliferation, was
downregulated rapidly after the induction of EVI1, suggesting that it
may be a direct target of this transcription factor, and may play a role
in its phenotypic effects .
The phenotypes observed after induction of EVI1 correspond well to
what would be expected for a gene involved in the pathogenesis of
MDS, and have also been observed with other MDS-associated oncogenes
. We have therefore established a suitable model system to
explore the role of EVI1 in the pathogenesis of this fatal disease .
P04.110
Familial myelodysplastic syndromes
A. Carrió 1,2 , A. Valera 1 , D. Costa 1 , I. Madrigal 2 , C. Gómez 1 , J. L. Aguilar 1 , M.
Aymerich 1 , D. Colomer 1 , B. Nomdedéu 3 , E. Montserrat 3,2 , E. Campo 1,2 ;
1 Hematopatology Unit Hospital Clínic, Barcelona, Spain, 2 IDIBAPS, Hospital
Clínic, Barcelona, Spain, 3 Hematology Department Hospital Clínic, Barcelona,
Spain.
The myelodysplastic syndromes (MDS) are a heterogeneous group
of clonal disorders of hematopoietic stem cells, whose manifestation
is cytopenia, hypercellular and dysplastic bone marrow, often with increased
amount of blasts . The pathogenesis of the majority of MDS
remains unexplained . It is regarded that genetic predisposition and exposure
to toxic environmental agents contribute to genetic mutations
in MDS .
We report an adult MDS family with 6 siblings, of which two presented
myelodysplastic syndrome (MDS), namely refractory cytopenia with
multilineage dysplasia (RCMD), at the ages of 37 and 49, respectively .
Conventional cytogenetics showed complex karyotypes, at diagnoses,
in both:
44,XX,del(5)(q13q33),-7,-9,der(15;21)(q10;q10),-21,+mar[9]/
46,XX[10] in the propositus, and 46,XY,-3,del(5)(q13q35),+8,der(12
)t(3;12)(q13;p13) [20] in the second one . The propositus developed
acute leukaemia and underwent an allogenic transplantation of peripheral
blood progenitor cells . She relapsed and eventually died of
sepsis eight months post-transplantation . In order to know the status
of the 4 other siblings, we performed morphological and cytogenetics
bone marrow analyses . Since del(5)(q31q33) was the only chromosomal
abnormality common to both complex karyotypes, we decided
to investigate all the samples by FISH with the specific probe for 5q31.
Surprisingly, we found that in the propositus the deleted chromosome
was an i(5)(p10;p10), and one of the healthy brothers showed 12% of
deletion 5q .
We postulate that in this family an inherited mutator effect is present
and that it causes a karyotype instability, which leads to MDS/AML,
with an unstable 5 chromosome .
P04.111
HFE C282Y mutation as a genetic modifier influencing disease
susceptibility for chronic myeloproliferative disease
H. Andrikovics 1 , N. Meggyesi 1 , A. Szilvasi 1 , J. Tamaska 2 , G. Halm 2 , S. Lueff 2 ,
S. Nahajevszky 2 , M. Egyed 3 , J. Varkonyi 4 , G. Mikala 2 , A. Sipos 2 , L. Kalasz 1 , T.
Masszi 2 , A. Tordai 1 ;
1 Hungarian National Blood Transfusion Service, Budapest, Hungary, 2 St. Istvan
and St. Laszlo Hospital, Budapest, Hungary, 3 Kaposi Mor Hospital, Kaposvar,
Hungary, 4 Semmelweis University, Budapest, Hungary.
The Janus kinase 2 (JAK2) V617F point mutation is a common clonal
alteration in chronic myeloproliferative disorders (CMPD) . Genetic
variations influencing susceptibility of CMPD have not been recognized
previously . The aim of our study was (i) to establish V617F mutation
status in CMPD patients (ii) to confirm associations with distinct
clinical characteristics, and (iii) to examine the potential associations
of CMPD development with genetic modifiers of iron metabolism (HFE
C282Y, H63D and TFR S142G) . HFE C282Y was genotyped in 328
CMPD-patients and 996 blood donors, HFE H63D and TFR S142G in
CMPD patients and 171 first time blood donors. JAK2 V617F mutation
was tested in CMPD patients and 122 repeated blood donors . The
frequency of JAK2 V617F was 75 .9% (249/328) in the CMPD group .
At presentation, significantly elevated hemoglobin levels were found
in V617F-positive patients compared to V617F-negative counterparts
(p