European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Cancer genetics
Although NB is characterized by numerous recurrent, large-scale
chromosome rearrangements, the genes targeted by these imbalances
have remained elusive. We recently identified the paired-like
homeobox 2B (PHOX2B, MIM 603851) gene as disease-causing in
dysautonomic disorders including Congenital Central Hypoventilation
Syndrome (CCHS), Hirschsprung disease (HSCR) and NB in various
combinations. Most patients with NB due to a germline heterozygous
PHOX2B gene mutation are familial and/or syndromic. PHOX2B, at
chromosome 4p12, does not lie in a commonly rearranged locus in
NB. To evaluate the role of PHOX2B in sporadic, isolated NB, we
analysed 13 NB cell lines and 46 tumors for mutations of coding and
promoter sequences, loss of heterozygosity (LOH), or aberrant hypermethylation
of PHOX2B (13 cell lines and 18 tumors). We identified no
mutation but LOH in about 10% of the cases and aberrant CpG island
methylation of the 500 bp PHOX2B promoter region in 4/31 (12.9%).
Altogether, both germinal and somatic anomalies at the PHOX2B locus
are found in NB.
P0602. Breast cancer and the promyelocytic leukemia gene
I. Jeziskova 1 , P. Plevova 1,2 , S. Walczyskova 1 , A. Krepelova 3 , K. Pavlikova 3 , V.
Kotala 4 , E. Silhanova 1 ;
1 University Hospital, Ostrava, Czech Republic, 2 Palacky University, Olomouc,
Czech Republic, 3 2nd Medical Faculty, Charles University, Prague, Czech Republic,
4 Weizmann Institute, Rehovot, Israel.
Introduction: The PML (promyelocytic leukemia) protein is a tumor suppressor
gene that encodes a multifunctional protein with critical tumor
suppressive functions such as induction of apoptosis, growth arrest
and cellular senescence. Its expression is downregulated in about one
third of tumors, including breast cancer. With respect to these facts we
tested the hypothesis that germline mutations of the PML gene might
predispose to breast cancer.
Patients and methods: Thirty five patients fulfilling the criteria for
BRCA1/BRCA2 gene mutation analysis in whom no germline BRCA1/
BRCA2 gene mutation was found were included into the study. Genomic
DNA was isolated from peripheral blood. Nine exons of the PML
gene were screened for mutations using heteroduplex analysis. Samples
with fragments of abnormal mobility were sequenced using ABI
prism 3100 genetic analyser.
Results: No germline mutation was found in the PML gene in any of
the patients.
Conclusion: Our results suggest that predisposition to breast cancer is
probably not associated with germline mutations of the PML gene. Acknowledgements:
The project was supported by IGA MZ CR NR/9092-
3/2006.
P0603. Array CGH of dic(7;9)(p11-13;p11-13) in B-cell precursor
acute lymphoblastic leukemia reveals clustered breakpoints at
7p11.2-12.1 and 9p13.2
C. Lundin1 , M. Heidenblad1 , B. Strömbeck1 , Å. Borg2 , R. Hovland3 , S. Heim4 , B.
Johansson1 ;
1 2 Dept of Clinical Genetics, Lund, Sweden, Dept of Oncology, Lund, Sweden,
3 4 Dept of Medical Genetics and Molecular Medicine, Bergen, Norway, Dept of
Medical Genetics, Oslo, Norway.
The dic(7;9)(p11-13;p11-13) is a recurrent chromosomal abnormality
in acute lymphoblastic leukemia (ALL), mainly of B-lineage. Although
more than 20 dic(7;9)-positive ALLs have been reported to date, the
molecular genetic consequences of this aberration are unknown.
We performed high-resolution (32K) genome-wide array-based comparative
genomic hybridization (array CGH) and locus-specific fluorescence
in situ hybridization analyses on three cases with dic(7;9)
in order to characterize the breakpoints on 7p and 9p. The analyses
showed a clustering of breakpoints at 9p13.1-13.2 in all three cases
and at 7p11.2 in two; the array CGH revealed two different breakpoints
- 7p12.1 and 7p14.1 - in the remaining case. Based on the present
results this abnormality should hence be designated dic(7;9)(p11.2-
12.1;p13.1-13.2). Unfortunately, lack of material precluded further molecular
genetic studies, and it thus remains to be elucidated whether
the pathogenetically important outcome of the dic(7;9) is formation of a
chimeric gene or loss of 7p and 9p material.
P0604. POET (Prevention of Endometrial Tumours), a
randomised control trial of the effect of the Mirena Intrauterine
System (IUS) with surveillance, versus surveillance alone, on
the development of atypical endometrial hyperplasia (AEH) and
carcinoma (EC) in women with Lynch Syndrome aged 35-65y.
S. V. Hodgson 1 , V. Murday 2 , P. Sasieni 3 , E. Sheridan 4 , T. Bourne 5 , E. Okaru 6 ;
1 St George’s, Tooting, London, United Kingdom, 2 Department of Medical Genetics,
Yorkhill NHS Trust, Glasgow, United Kingdom, 3 Wolfson Institute, Queen
Mary University of London, London, United Kingdom, 4 Yorkshire Regional Clinical
Genetics Service,St James’ University Hospital, Leeds, United Kingdom,
5 Dept. Gynaecology, St.George’s Hospital, London, United Kingdom, 6 Dept.
Gynaecology, Barts and the London NHS Trust, St.Bartholomew’s Hospital,,
London, United Kingdom.
Women with Lynch syndrome have an increased risk of developing endometrial
cancer (up to 65% lifetime risk, 20% before 50y). The Mirena
progestogen-releasing intra-uterine system greatly reduces the thickness
of the endometrium. This study proposes to evaluate whether
treatment with the Mirena for 4y reduces the rate of detection of AEH
and EC in women with Lynch Syndrome on surveillance by annual
transvaginal ultrasound (TVS) and EB. Secondary study outcomes include
determination of the sensitivity and specificity of surveillance, the
age-related incidence of AEH and EC in women with Lynch syndrome,
the premalignant pathway to carcinoma, the psychological effects of
this management protocol and any adverse effects of surveillance and
use of the Mirena IUS. We piloted the Mirena IUS for 6 months in 15
women, average age 42y (24-56y). 9 experienced mild, 4 moderate
and 2 severe pain on insertion. One IUS was removed for excess uterine
bleeding; 7 women had spotting and 7 no endometrial bleeding.
EB was successful before and after the trial period; all post-Mirena
biopsies showed decidualisation of the endometrium. 5 women chose
to continue for longer with the Mirena.
This study is funded by CR-UK for 5y. in the UK, where we have initiated
it as a multi-centre National study. We welcome expressions of
interest to initiate wider international collaboration.
P0605. Detection of PML-RARA rearrangement by RT-PCR in an
acute promyelocytic leukemia without evidence by FISH.
S. Ramiro 1 , O. González 1 , C. Blas 1 , M. Renedo 1 , C. Castellanos 1 , L. de la
Vega 1 , M. Calderón 1 , C. Martinez-Chamorro 2 , P. Font 2 , C. Alaez 2 , A. Alegre 1 , A.
Escudero 2 , E. Arranz 1 ;
1 Gemolab, Madrid, Spain, 2 Ruber Hospital, Madrid, Spain.
Acute promielocytic leukemia (APL) is characterized by a reciprocal
translocation, t(15;17), resulting in fusion of the genes promyelocytic
leukemia (PML) and retinoic acid receptor alpha (RARA). This translocation
is detected in about 70-90% of patients by conventional cytogenetic
methods. There are also masked or cryptic t(15;17) that may be
generated by submicroscopic insertions of PML or RARA or more complex
rearrangements. Those masked PML-RARA fusions can be identified
by molecular analyses such reverse transcriptase-polimerase
chain reaction (PCR) and fluorescence in situ hybridization (FISH).
We have studied the case of a 55-years-old woman that shows clinical,
morphological and inmunophenotypic features of APL. The PML-
RARA was not evident on FISH test, while RT-PCR revealed the presence
of PML-RARA transcript (bcr-3). The probe used was PML-RARA
dual color dual fusion (Vysis). It was not possible to perform the chromosomal
analyses because of the coagulation of the sample of bone
marrow. The patient was treated with a standard protocol for APL that
includes All Trans Retinoic Acid (ATRA) and chemotherapy.
The FISH probes used in this case are a good molecular testing to
detect cryptic, variants or complex PML-RARA rearrangements, but
depending on the size of the insertion of PML-RARA, the target could
be so small that it would not hybridize with the probe or even hybridization
itself might not generate a fluorescent signal large enough to
be visualized by FISH. Thus, a combination of molecular testing FISH
and PCR could avoid false negative results in presence of masked
PML-RARA fusions.
P0606. Overexpression of CD2 and c-myc in prostate cancer
tissue samples obtained by needle biopsy.
A. Szendrői, B. Nagy, Z. Papp, I. Romics;
Semmelweis University, Budapest, Hungary.
Objective: Altered CD24 and c-myc expression was reported in different
cancers. We decided to establish a quantitative real-time PCR
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