2008 Barcelona - European Society of Human Genetics

Cancer genetics
deleterious mutations . Many routine detection techniques are available,
but none gives a panoramic view of the gene and characterizes
breaking points .
We have developed a zoom-in array-CGH for detecting and characterizing
rearrangements based on Agilent® high-resolution oligonucleotide
array-CGH technology . The Centre René Huguenin designed
three specific arrays for the BRCA1 (1679 oligonucléotides) & BRCA2
(1389), MLH1 (1031) & MSH2 (789) and APC (1573) genes .
Prior to use this approach in routine, we analyzed 18 DNA samples
with a large deletion or duplication detected with QMPSF, MLPA or
qPCR : 10 BRCA1/BRCA2, and 3 MLH1/MSH2 from Centre René Huguenin
and 4 APC from Institut Paoli Calmettes .
All the large rearrangements from single small exon to the whole gene
were detected (size estimated to within 1-2 kb) . Five never-reported
events were characterized (table) . Except for the whole APC gene deletion,
the event was characterized thanks to a simple PCR .
Zoom-in Array-CGH described here gives the opportunity to rapidly
screen a group of genes involved in breast and colorectal cancer . Despite
its cost, this method can assist with the development of simple
PCR-based genetic test. Additional studies are needed to define its
position in routine testing .
Five new germline large rearrangements characterized with zoom-in
array-CGH and sequencing
Genes Events size
BRCA deletion exon 3 11 452 bp
BRCA duplication exons 17-20 14 756 bp
APC deletion exons 12-14 6 360bp with insertion 351bp
MLH duplication exon 4 1 664 bp
MSH deletion exons 8-10 26 349 bp
P04.047
Estrogen receptor-α (ESR ) gene polymorphisms in iranian
women with breast cancer: a case control study
S. Abbasi 1 , P. Ismail 2 , F. Othman 2 , C. Azimi 3 , R. Omranipoor 4 , Z. Ousati
Ashtiani 5 , M. Mojarrad 5 , S. Abdi-Oskouie 5 , F. Mahboubi Nejad 5 ;
1 School of Allied Medical Sciences, Medical Sciences / University of Tehran,
Tehran, Islamic Republic of Iran, 2 Department of Biomedical Science, Faculty
of Medicine and Health Science, Universiti Putra, Serdang, Malaysia, 3 Department
of Genetics, Cancer Institute, Imam Khomeini Medical Center, School of
Medicine, Medical Sciences / University of Tehran, Tehran, Islamic Republic of
Iran, 4 Department of Surgery, Cancer Institute, Imam Khomeini Medical Center,
School of Medicine, Medical Sciences / University of Tehran, Tehran, Islamic
Republic of Iran, 5 Department of Medical Genetics, School of Medicine, Medical
Sciences / University of Tehran, Tehran, Islamic Republic of Iran.
Receptor-mediated estrogen activation participates in the development
and progression of breast cancer . Evidence suggests that alterations
in estrogen signaling pathways, including ESR1 occur during breast
cancer development . ESR1 polymorphism has been found to be associated
with breast cancer in Caucasians . Epidemiologic studies have
revealed that age-incidence patterns of breast cancer in Middle East
differ from those in Caucasians . Genomic data for ESR1 in either population
is therefore of value in the clinical setting for that ethnic group
and we have investigated whether polymorphisms in the ESR1 are
associated with breast cancer risk .
A case-control study was conducted to establish a database of ESR1
polymorphisms in Iranian population in order to compare Western and
Iranian distributions and to evaluate ESR1 polymorphism as an indicator
of clinical outcome . The ESR1 gene was scanned in Iranian patients
newly diagnosed invasive breast tumors,(150 patients) and in healthy
individuals (147 healthy individuals) . PCR single-strand conformation
polymorphism technology and 33 P-cycle sequencing was performed .
The sets of silent single nucleotide polymorphisms were found, as reported
previously in other studies, but at significantly different frequencies
. Among these SNPs, the frequency of allele 1 in codon P325P
(C1337G) was higher in breast cancer patients (10 .3%) than in control
individuals (8 .8%; P =0 .538), although the difference was not statistically
significant. The allele 1 in codon H267L (A1162T) exhibited an association
with the occurrence of family history of cancer among breast
cancer (0 .8%; P=0 .004) .
Our data suggest that ESR1 polymorphisms are correlated with various
aspects of breast cancer in Iranian ESR1genotype .
P04.048
EmQN Best Practice Guidelines for molecular Analysis in
Hereditary Breast/Ovarian Cancer
N. E. Larsson 1 , Å. Borg 2 , O. Sinilnikova 3 , S. Hodgson 4 , C. Müller-Reible 5 , U.
Kristoffersson 1 ;
1 Department of Genetics, Lund University Hospital, Lund, Sweden, 2 Department
of Oncology, Lund University Hospital, Lund, Sweden, 3 3Unité Mixte
de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de
Lyon-Centre Léon Bérard, Lyon, France, 4 4Department of Cancer Genetics,
St George’s Hospital, University of London, London, United Kingdom, 5 Department
of Human Genetics, University of Würzburg, Würzburg, Germany.
Breast cancer is the most frequent form of cancer in women . Genetic
predisposition underlies 5-10% of all breast cancer and up to 40% of
cases in patients under the age of 35 years . The discovery of BRCA1
and BRCA2 in 1994 and 1995, respectively, was anticipated to greatly
increase our knowledge of hereditary breast cancer . This was immediately
followed by an increasing demand for genetic testing from health
care to predict future cancer risks . Since then, breast cancer genetics
has become a major part of the workload of clinical genetics clinics .
The identification of the BRCA1/2 mutations and the communication
of the genetic information are essential for women at high risk
for breast cancer . As a result, guidelines for genetic counselling and
laboratory quality assessment in cancer genetics have been developed
at local and national levels both in Europe and in the USA . The
European Molecular Genetics Quality Network (EMQN) drafted best
practice guidelines on breast/ovarian cancer genetic testing as a first
attempt towards European harmonisation in 1999 . In 2007, OECD has
issued general recommendations for molecular genetic testing . The
best practice guidelines presented here are the results of discussions
among European breast cancer geneticists at a workshop in Würzburg,
Germany, October 24-25, 2007 with the aim of updating the 1999
EMQN guidelines .
P04.049
HFE and TFR polymorphisms in the risk of breast cancer in são
miguel population (Azores, Portugal)
P. R. Pacheco1,2 , M. J. Brilhante1 , C. Ballart1 , T. Eloi1 , C. C. Branco1,2 , R. Cabral1,2
, V. Santos1 , V. Carneiro1 , L. Mota-Vieira1,2 ;
1 2 Hospital Divino Espirito Santo de Ponta Delgada, EPE, Azores, Portugal, Instituto
Gulbenkian de Ciência, Oeiras, Portugal.
Iron overload has been noticed as a feature of breast cancer (BC) .
HFE mutations, which lead to iron uptake increase, have been evaluated
as risk factor . Some studies concluded that BC risk increase is also
dependent on HFE-interacting genes, such as the transferrin receptor
(TFR) and the combination between HFE-TFR genotypes .
To assess if HFE mutations, TFR-S142G polymorphism and HFE-TFR
genotypes are related to BC risk, we compared C282Y, H63D and
S142G frequencies in 86 BC women and in 183 gender/age matched
healthy controls . Samples were obtained after written informed consent
.
The C282Y allele frequency in the BC group was 4 .07%, higher than
in control group, 3 .28%; while H63D mutation showed a similar frequency
in BC, 21 .51%, and controls, 21 .04% . Although both groups
were stratified according to menopausal status, odds ratio (OR) analysis
for cancer risk associated with HFE mutations was not statistically
significant. Regarding S142G polymorphism, the frequency of S142S,
S142G and G142G genotypes were equivalent in both groups . In order
to extend the search for a supposed BC susceptibility for HFE-TFR
genotypes, we analysed BC and controls according to compound genotypes
. Again, OR for all HFE-TFR genotype combinations revealed
no increased risk for BC .
In conclusion, the results suggest that HFE mutations are not associated
with an increased risk for BC . TFR polymorphism was not an
independent risk factor and did not modify the disease risk . Furthermore,
variants of the HFE-TFR have, apparently, no direct effect on the
incidence of breast cancer in the Azorean female population .
0