2009 Vienna - European Society of Human Genetics

Cancer genetics
preferentially duplicated or amplified leading to up-regulated expression,
contribute to tumour progression, and are associated with adverse
outcome.
P06.199
A novel chromosomal translocation t(11;14)(q24.1;q32)
involving iGH in childhood B-cell precursor acute lymphoblastic
leukaemia (BcP-ALL)
E. Tassano, M. Acquila, E. Tavella, C. Rosanda, C. Panarello, C. Morerio;
IRCCS Istituto G.Gaslini, Genova, Italy.
Rearrangements involving IGH gene on chromosome 14q32.3 are well
known in mature B-cell malignancies and have been more recently
described in BCP-ALL. IGH translocations are usually reciprocal and
bring genes on other chromosomes into close apposition with the IGH
locus, where their expression is deregulated due to the presence of
potent B-cell-specific transcriptional enhancers. A two-year-old girl was
diagnosed with an ALL common type and treated according to AIEOP-
ALL-00 Protocol. Death occurred after four months due to haematological
toxicity. Cytogenetic analysis of PB and BM blasts revealed a
t(11;14)(q24∼32;q32). FISH analysis with IGH break-apart probe confirmed
the rearrangement of the IGH locus between chromosomes 11
and 14. Cloning by LDI-PCR localized the breakpoint on chromosome
11q24.1 within the intronic region 1 of BC089451, a non coding gene.
Quantitative real-time PCR showed over-expression of BLID mRNA,
located 14Kb downstream the BC089451 gene. BLID codes for a protein
containing a BH3-like domain essential for apoptosis. FISH studies
performed with 11 close BACs to confirm the breakpoint junction
identified a 585Kb deletion on der(11), with complete SORL1 loss. The
functional consequence of BLID over-expression due to IGH enhancer
juxtaposition is currently unknown. Mutational analysis of BLID BH-3
like domain is ongoing. The translocation to the Ig locus may result not
only in deregulated expression of the incoming oncogene, but also in
mutations due to the action of the Ig somatic hypermutation mechanism.
In our case, a mutation of BLID in BH3 domain could result in a
protein not inducing apoptosis.
P06.200
Four new chromosomal translocation in B-cell chronic
lymphocitic leukemia
A. Carrió, D. Costa, C. López, A. Arias, A. Varela, N. Villamor, D. Colomer, M.
Rozman, F. Bosch, E. Montserrat, E. Campo;
Hospital Clínic, Barcelona, Spain.
B-cell chronic lymphocitic leukemia (B-CLL) is the most common type
of leukemia in the Western countries and is characterized by the clonal
expansion of morphologically mature small lymphocytes. Clonal chromosome
abnormalities in B-CLL are detected in 40-50% of cases by
conventional cytogenetics after mitogen stimulation.
We report four novel chromosomal translocations identified by conventional
cytogenetic in four patients with B-CLL.
All patients were male. Clinical, laboratory and inmunophenotipic data
were consistent with B-CLL diagnosis. Cytogenetic studies were carried
out in peripheral blood (PB) using 12-O-tetradecanoylphorbol-13acetate
(TPA) as mitogen. Cultures were maintained for 3 days in CO 2
atmosphere.
The karyotypes were:
Case 1:
46,XY,t(1;7)(q34;q11)[2]/46,XY[18].
Case 2:
45,XY,der(7,14,15)t(7;14)(p10;q32)t(7;15)(p10;q10),del(11)(q22q23)
[2]/44,idem,der(13;14)(q10;q10)[6]/46,XY[11].
Case 3:
46,XY,-8,der(17)t(8;17)(q10;p13)[8]/46,XY[6].
Case 4:
46,XY,t(15;22)(q26.1;q11.2)[13]/46,XY[7]
A search in the National Cancer Institute Mitelman Database of Chromosome
Aberrations in Cancer revealed that none of the translocations
reported herein has previously been described in B-CLL.
Cytogenetic analysis of B-CLL patients, despite inherent technical limitations,
has provided important information on disease biology and clinical
outcome. Thus, B-CLL associated chromosomal aberrations will
be identified at increased frequencies, possibly enabling more precise
definition of cytogenetic risk subgroups and providing new prognostic
markers.
P06.201
New variant of BCR/ABL translocation, t(4;9;22) identified at the
onset of chronic myeloid leukemia - case report
A. Lungeanu1 , A. Arghir1 , S. Chirieac1 , G. Cardos1 , M. Ciochinaru2 ;
1 2 Victor Babes National Institute of Pathology, Bucharest, Romania, “Carol
Davila” Central Military Hospital, Bucharest, Romania.
Variant forms of Philadelphia (Ph) positive patients with chronic myeloid
leukemia (CML) characterize ~ 5-12% of cases. The variant
translocations involve one or more chromosomal regions in addition
to 9q34 and 22q11.
Here we present a variant translocation, t(4;9;22) found in a patient
with chronic myeloid leukemia, at the time of initial diagnosis.
Classical cytogenetics and fluorescence in situ hybridization (FISH)
with WCP 9(R), WCP 4(G), WCP 22(R), BCR/ABL double fusion
(Poseidon-Kreateck) and BAC/cosmid n85a3 (22q13.3), RP11-492I23
(4p16.3) probes were used to study the mechanism of variant Ph
translocation.
Philadelphia chromosome was visible in all bone marrow cells by conventional
cytogenetic analysis and karyotypes showed two other derivative
chromosomes which could not be elucidated by GTG banding.
By RT-PCR, a b3a2 transcript was revealed, with the cDNA amplycon
shorter (between 300 and 350bp) than positive control (388bp), possible
the breakpoint is into b3 exon of BCR gene.
FISH analysis allowed us to establish the following karyotype formula:
46,XY,t(4;9;22)(q21;q34;q11). ish t(4;9;22) (wcp4+,wcp22+,BCR+,
RP11 -492 I 23 +, n 85a3 ;wcp9+,wcp4+,ABL+,BCR-; wcp22+,
BCR+,ABL+).
Our results underline the necessity to accomplish the karyotype investigation
by molecular and FISH techniques to prevent the erroneous
reporting and inappropriate disease management.
Acknowledgments
The authors thank Prof. Dr. Jean-Michel Dupont and Mrs. Dominique
Blancho for kindly providing BAC probes and Mrs. Marioara Cristea for
technical assistance.
P06.202
Putative association of polymorphisms in DNA repair genes with
cytogenetic subgroups in B-cell chronic lymphocytic leukaemia
C. Ganster1 , J. Neesen1 , U. Jäger2 , H. Esterbauer3 , C. Mannhalter3 , C. Fonatsch1
;
1Department of Medical Genetics, Medical University of Vienna, Vienna, Austria,
2Division of Hematology and Hemostaseology, Department of Internal
Medicine I, Medical University of Vienna, Vienna, Austria, 3Clinical Institute of
Medical and Chemical Laboratory Diagnostics, Medical University of Vienna,
Vienna, Austria.
Genetic polymorphisms in DNA repair genes may influence the susceptibility
to different forms of cancer. Therefore we investigated the
association of seven SNPs in five DNA repair genes with the incidence
of chronic lymphocytic leukaemia (CLL). We analysed 461 CLL patients
and an equal number of sex and age matched controls using
PCR followed by digestion with restriction enzymes. The odds ratios
(OR) and P-values were calculated by logistic regression analysis. As
chromosomal aberrations are important prognostic markers in CLL,
we paid particular attention to 133 patients with the favourable cytogenetic
aberration del(13q) as sole aberration and 69 patients with
the unfavourable cytogenetic aberrations del(17p) and del(11q). The
rare genotypes of rs13181 in the nucleotide excision repair gene xeroderma
pigmentosum D (XPD) and rs25487 in the base excision repair
gene X-ray repair complementing defective repair in Chinese hamster
cells 1 (XRCC1) occurred significantly more frequently in patients with
unfavourable cytogenetic aberrations compared to controls: The genotypes
of rs13181 were differently distributed under the co-dominant
model (A/A vs. G/G: OR = 2.66, p = 0.024) and those of rs25487 under
the dominant model of inheritance (A/C and C/C vs. A/A: OR = 2.44,
p = 0.01). Additionally, significant differences in the genotype distribution
of rs13181 were observed between all patients and controls (A/C
and C/C vs. A/A: OR = 1.37, p = 0.03). Our results indicate that inborn
polymorphisms in DNA repair genes may help to predict the outcome
of CLL. We are verifying them now by correlation with survival data.