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

Cancer genetics
In summary within 156 Slovak breast/ovarian families, we identified
34 families (21,8%) with pathologic germline BRCA1 and BRCA2 mutations.
A novel BRCA1 mutation c.1166delG was not previously described
in BIC database and published until year 2006 and we suspect
it is of Slovak origin.
P0509. Germline BRCA2 large rearrangements are not a
common cause of breast/ovarian cancer predisposition
S. Pagès-Berhouet1 , S. Reynaud1 , V. Caux-Moncoutier1 , D. Michaux1 , A. Laugé1
, A. De Pauw1 , M. Gauthier-Villars1 , D. Stoppa-Lyonnet1,2 , C. Houdayer1,3 ;
1 2 3 Institut Curie, Paris, France, INSERM U509, Paris, France, UMR INSERM
745, Paris, France.
Screening for large deletions and duplications of the BRCA1 gene is
now recognized as an important part of routine molecular diagnosis in
familial breast/ovarian cancer. The picture is less clear as to the value
of screening BRCA2 for such alterations. The available studies seemingly
show that this is a worthwhile screening however they are based
on patients selected for high probability of breast/ovarian cancer predisposition.
No data are available for patients routinely ascertained in
genetic units.
Therefore we embarked upon BRCA2 large rearrangement screening
on a large sample of 488 patients consecutively ascertained in
our breast cancer family clinic for whom breast/ovarian cancer genetic-predisposition
was 1%-96% (mean 53%) according to the Claus
model. Obviously all these patients were tested negative for BRCA1
point mutations and large deletions and for BRCA2 point mutations.
BRCA2 large rearrangement screening was performed using a previously
published QMPSF assay and included control samples bearing a
BRCA2 deletion and a trisomy 13 purchased from Corriel. All controls
were successfully identified and no BRCA2 rearrangement was found
in these 488 patients.
These results strongly suggest that BRCA2 large rearrangements are
not a common cause of breast/ovarian cancer predisposition. Oncogenetic
teams should now discuss if this screening should be proposed
on a routine basis or only to highly selected patients. It could also be
used as a second-line screening however this option could greatly delayed
the results availability to the detriment of the genetic follow-up.
P0510. Breast cancer susceptibility association with a regulatory
SNP in 3’utr region of E2F1 gene
E. Barroso 1 , E. Wentzel 2 , R. L. Milne 1 , J. Arias 3 , P. Zamora 4 , J. T. Mendell 2 , J.
Benítez 1 , G. Ribas 1 ;
1 CNIO, Madrid, Spain, 2 The McKusick-Nathans Institute of Genetic Medicine,
Baltimore, MD, United States, 3 Monte Naranco Hospital, Oviedo, Spain, 4 La
Paz Hospital, Madrid, Spain.
SNPs located in regulatory regions (rSNPs) have been proposed as
potential causal SNPs in complex traits and diseases because of their
role in modulating gene expression.
In the current work, we present the research on a rSNP located in 3’utr
of E2F1, rs3213180, within a case-control association study, using up
to 854 sporadic breast cancer patient and 553 control samples. A relative
risk of 2.3 (95%C.I.=0.48-11.10), was estimated for rs3213180, not
statistically significant, possibly due to the low Spanish MAF=0.05. It
has been described that the expression of the E2F1 gene is modulated
by c-Myc, which activates E2F1 transcription, but also blocks its translation
through the activation of transcription of some miRNAs. These
miRNAs recognize two binding sites at the 3’utr region of the E2F1
mRNA and delay the translation to protein, and rs3213180 is located
at the 3’utr region, upstream of binding site 2.Luciferase expression
assays using constructs with E2F1 3’utr have revealed a mild increment
in expression in the presence of the minor allele (p-value