2008 Barcelona - European Society of Human Genetics

Cancer genetics
Research Centre, Moskow, Russian Federation.
Bilateral breast cancer (BiBC) is considered as phenotypic sign of inherited
breast cancer risk . However it is unknown if there any peculiarities
of familial breast cancer (BC) with cases of BiBC .
We investigated BRCA1/2 mutations among 38 patients with BiBC
who had one or more relatives with BC or ovarian cancer (OC) . The
BRCA1/2 mutations were found among 19 patients (50%) . The BRCA1
gene mutations were predominant (16 of 19, 84%) with prevailing
5382insC (9 of 16, 56%) . Two BRCA1 gene mutations - 3411delCT
and 3747insA and three BRCA2 mutations - P3039P, 9498delC,
886delGT were revealed in Russia for the first time. Among 10 BC/
OC families there were 6 BRCA1 mutations that fully correspond to
60% defined earlier for the same families without BiBC. Among BiBC
families with BC only 36% had BRCA1 mutations . For comparison,
among 92 BC families unselected on BiBC there were 21% mutations .
Another words, BRCA1 mutations in BiBC families more frequently
predispose to BC only than in families without BiBC . Beside this, there
were 10 cases of repeated BiBC in 8 families and all of them were BC
only families . It may be proposed that in some families with BiBC there
is genetic influence that modify risk of cancer localization. In part supported
by grant RFBR N 07-04-01602 .
P04.055
High frequency of BRcA1 gene mutations among patients with
pregnancy associated breast cancer
A. N. Loginova1 , L. N. Lubchenko2 , A. A. Parokonnaya2 , A. A. Lushnykova2 , R.
F. Garkavtseva2 , N. I. Pospekhova1 , A. V. Karpukhin1 ;
1 2 Research Centre For Medical Genetics, Moskow, Russian Federation, Cancer
Research Centre, Moskow, Russian Federation.
A relationship between a pregnancy and breast cancer risk is a subject
of studying at last time . The reasons for breast cancer onset during a
pregnancy are not clear at present time . A role of BRCA1/2 mutations
in pregnancy associated breast cancer (PABC) onset is not well estabilshed
. We studied the most frequent in Russia BRCA1 mutations
5382insC, C61G and 185delAG in a sample of 74 patients with PABC
and in a control sample of 75 breast cancer patients . A control sample
was adjusted on age of diagnosis among PABC patients (an average
age 33 year) . There were 12 of 74 PABC patients with BRCA1 mutations
(16%) . The patients with 5382insC mutation were predominant
(11 of 12) . For all but one of 12 PABC patients breast cancer was
diagnosed during second or futher pregnancy . Among patients of control
sample there were 6 with mutations (8%), all 5382insC . The high
BRCA1 mutation frequency among PABC patients could connected
with some peculiarities of this patient group . We found that the age of
diagnose for BRCA1-associated breast cancer among PABC patients
was in interval 26-35 years while among patients of control group -
33-46 years . Thus the high frequency of BRCA1 mutations and early
breast cancer onset among PABC patients is suggestive on undetermined
now genetics or phenotypic peculiarities that may increased
breast cancer risk during a pregnancy .
P04.056
CLSPN gene in hereditary susceptibility to breast cancer
H. Erkko1,2 , K. Pylkäs1,2 , S. Karppinen1,2 , R. Winqvist1,2 ;
1 2 Laboratory of Cancer Genetics, University of Oulu, Oulu, Finland, Biocenter
Oulu, Oulu, Finland.
Approximately 5-10 % of breast cancer is thought to be due to an inherited
disease predisposition . Mutations in currently known cancer
susceptibility genes explain only 20-30% of the familial cases, which
suggests the contribution of additional genes . Claspin, encoded by the
CLSPN gene, is involved in monitoring of replication and sensoring
of DNA damage, during which it cooperates with CHK1, BRCA1 and
ATR. As many previously identified susceptibility factors act in similar
functional pathways as claspin, CLSPN is a plausible candidate gene
for heritable breast cancer susceptibility . Here we have screened the
entire coding region of the CLSPN gene for mutations in affected index
cases from 125 Finnish families with breast and/or ovarian cancer
using conformation sensitive gel electrophoresis (CSGE) and direct
sequencing . Several sequence changes were observed, but none of
them appeared to significantly associate with breast cancer susceptibility.
To our knowledge, this is the first study reporting the mutation
screening of the CLSPN gene in familial breast cancer cases .
P04.057
BRcA1-c.5272-1G>A and BRcA2-c.5374_5377deltAtG are
Founder Mutations in the East of Castilla-León (Spain)
M. Infante 1 , M. Duran 1 , L. Pérez-Cabornero 1 , D. J. Sanz 1 , E. Lastra 2 , C. Miner 1 ,
E. Velasco 1 ;
1 IBGM, Valladolid, Spain, 2 Hospital General Yagüe, Burgos, Spain.
The incidence of germline mutations in BRCA1 and BRCA2 genes in
high-risk families for hereditary breast and/or ovarian cancer varies
among different populations; presenting a wide spectrum of unique
mutations, whereas in other groups specific mutations show a high frequency
due to a founder effect . The mutations c .5272-1G>A in BRCA1
and c .5374_5377delTATG in BRCA2 are the most prevalent in our region;
they have been identified seven and nine times, respectively,
in our population suggesting the existence of founder effects in our
region .
Six highly polymorphic markers spanning BRCA1 (D17S800,
D17S1185, D17S855, D17S1323, D17S1325 and D17S579) and four
in BRCA2 (D13S171, D13S260, D13S1695 and D13S1698) were genotyped
in 16 index cases and additional family members . The estimation
of founder mutation age in generations was calculated using the
equation G= log δ/ log (1-θ) 1 .
All carriers of c .5272-1G>A shared the same alleles at the six markers
of BRCA1 .We could not estimate the age of the mutation because
the lack of recombinant markers that are required for this purpose . A
conserved haplotype was observed in c .5374_5377delTATG positive
families between the two external markers (approximately 1 Mb interval)
. The mutation occurred approximately 36 generations (900 years
assuming 25 years per generation) . The corresponding haplotype of
each mutation were absent in non-carriers and 75 healthy controls
supporting the hypothesis of a common ancestry . Conclusively, mutations
c .5272-1G>A for BRCA1 and c .5374_5377delTATG for BRCA2
are founder in our region .
1 Risch N . et al, Nat Genet 9:152-159, 1995 .
P04.058
tissue microarray analysis of 1q21.3 and 1q23.3 copy number
changes in ovarian tumors with different clinicopathological
parameters
I. Dimova 1 , B. Orsetti 2 , R. Dimitrov 3 , S. Raicheva 4 , N. Doganov 3 , C. Theillet 2 , D.
Toncheva 1 ;
1 Department of medical genetics, Sofia, Bulgaria, 2 INSERM U868, Montpellier,
France, 3 University Hospital of Obstetrics and Gynecology, Sofia, Bulgaria,
4 Laboratory of Gynecopathology, Sofia, Bulgaria.
Many studies reported that aberrations like amplifications, deletions
and translocations of 1q21-q23 have been found in ovarian tumors .
These findings increase the scientific interest in analyzing this region
by means of specific gene probes. The object of our study was to investigate
the frequency of copy number changes of two specific BAC
clones in 1q21 .3 and 1q23 .3 in large number ovarian tumors from
different malignancy, histology, stage and grade, arranged in tissue
microarrays, in order to analyze their correlation with tumor phenotype
. Copy number changes of 1q21 .3 were established in 9 .64% of
malignant, in 8 .33% of LMP and in 13 .13% of benign ovarian tumors .
Copy number changes of 1q23 .3 were found in 17 .78% of malignant,
in 16 .67% of LMP and in 12 .64% of benign ovarian tumors . We have
found significantly more frequent gain of 1q23.3 in non-epithelial tumors
(50%) compared to epithelial ones (14 .73%) (p