2009 Vienna - European Society of Human Genetics

Cancer genetics
Materials and methods: We have screened index cases from 65 highrisk
breast cancer families for germ-line mutations in exons 2, 11 and
20 of the BRCA1 gene. Mutation analysis was performed by direct
sequencing using 14 primer pairs covering the coding sequences and
their intron-exon junctions.
Results: The founder mutations described in Ashkenazi Jews:
5382insC in BRCA1 exon 20 was observed in 6 patients from families
with multiple cases of breast/ovarian cancer. Three of the patients
have developed both breast and ovarian cancer, two were with early
onset, and one had both early onset and bilateral breast cancer. In
addition we found one unknown missense alteration in exon 11, codon
1037 (T>C), that leads to replacement of Val with Ala in patient with
bilateral breast cancer developed by the age of 45.
Conclusions: It has been known that Ashkenazi Jews 5382insC founder
mutation is spread all over Central and Eastern Europe ant it is the
most common in breast/ovarian cancer families from Hungary, Poland,
Yugoslavia, Latvia, Italy, Spain, Greece and Russia. Our results suggest
that the 5382insC might be also one of the most frequent mutations
among breast/ovarian cancer families in Bulgaria.
One unknown missense mutation in codon 1037 (T>C)of BRCA1 exon
11 was also identified. The possible functional relevance of the mutation
will be further studied.
P06.112
Descriptive study of French large rearrangements in BRCA
gene involving the promoting area
E. Rouleau 1 , A. Briaux 1 , C. Delnatte 2 , D. Muller 3 , S. Mazoyer 4 , L. Castera 5 , C.
Houdayer 5 , F. Coulet 6 , V. Bourdon 7 , S. Krieger 8 , I. Bieche 1 , N. Uhrhammer 9 , A.
Hardouin 8 , Groupe Génétique et Cancer Sein, D. Stoppa-Lyonnet 5 , R. Lidereau
1 ;
1 Centre René Huguenin, St Cloud, France, 2 CHU Nantes, Nantes, France,
3 Centre Paul Strauss, Strasbourg, France, 4 UMR 5641 CNRS-Université
Claude Bernard, Lyon, France, 5 Institut Curie, Paris, France, 6 Hôpital Pitié
Salpêtrière, Paris, France, 7 Institut Paoli-Calmettes, Marseille, France, 8 Centre
François Baclesse, Caen, France, 9 Centre Jean Perrin, Clermont-Ferrand,
France.
The BRCA1 gene is implied in the breast and ovarian cancer predisposition.
10-15% of deleterious mutations are large rearrangements
involving one or several exons. In the French BRCA1 database, 28 out
of 403 deleterious mutations are large rearrangements. The 5’ flanking
region of the gene contains a BRCA1 pseudo-gene which could ease
rearrangements. Up to now, only three large rearrangements involving
the promoting area of the gene have been described in the litterature.
In this study, we characterize 18 large rearrangements in this promoting
region from French families with a zoom-in dedicated array-CGH
(3107 oligonucleotides) and sequence the breaking points.
We found 11 never described events from 6kb to 238kb. There were
2 deletions from 5’ to promoting region, 13 deletions from 5’ to exon 2
and 3 deletions from 5’ to other exons (exon 3, 17, full BRCA1). Two
families have a rearrangement described in the literature (14kb and
37kb). A deletion to exon 2 was recurrent in 3 families. Two involved
only the promoting area of the gene and not the coding sequence (5kb
and 209kb).
The analysis of the breaking points revealed some redundant break regions
which could improve the understanding of those events. Thanks
to the efficacy of the dedicated array-CGH, the analysis confirms the
diversity and the recurrence of the large rearrangements involving the
promoting area.
P06.113
the BRcA1/2 mutations and sNPs in ovarian cancer risk
T. Y. Smirnova1 , N. I. Pospekhova1 , A. N. Loginova1 , L. N. Lubchenko2 , R. F.
Garkavtseva2 , E. K. Ginter1 , A. V. Karpukhin1 ;
1 2 Research Centre For Medical Genetics, Moscow, Russian Federation, Cancer
Research Centre, Moscow, Russian Federation.
Germline mutations in the BRCA1 and BRCA2 genes confer increased
susceptibility to ovarian cancer. We analyzed BRCA1/2 mutations
among ovarian cancer patients with familial history of breast/ovarian
cancer and among unselected on familial history ovarian cancer
patients. Among 101 unselected on familial history ovarian cancer
patients in Russian population there were 17 cases with BRCA1/2
mutations (16,8%). In order to find variants that may have influence
on ovarian cancer risk three samples of patients on the base of mu-
tation analyses were formed and analyzed: ovarian cancer without
BRCA1/2 mutations, BRCA1-associated ovarian cancer and control
sample. Several moderate penetrance cancer risk BRCA1/2 variants
were investigated. It was shown that genotype 203A/A in BRCA2 gene
was associated with increased ovarian cancer risk for both sporadic
and BRCA1-associated ovarian cancer (OR=5,8; p=0,003). There
was no confirmation of cancer risk modification by genotype 203A/A
in a samples of patients with sporadic and BRCA1-associated breast
cancer. The results demonstrate that defined genotype on SNPs may
have influence on increasing ovarian cancer risk both sporadic and
BRCA1-associated.
P06.114
the effect of cHEK2 missense variant i157t on the risk of breast
cancer in carriers of other cHEK2 or BRcA1 mutations
J. Lubinski 1 , C. Cybulski 1 , B. Górski 1 , T. Huzarski 1 , T. Byrski 1 , J. Gronwald 1 , T.
Dębniak 1 , D. Wokołorczyk 1 , A. Jakubowska 1 , P. Serrano Fernández 1 , T. Dork 2 ,
S. Narod 3 ;
1 Pomeranian Medical University, Szczecin, Poland, 2 Hannover Medical School,
Hannover, Germany, 3 Womens College Research Institute, Toronto, ON,
Canada.
Purpose: It is of interest to estimate the breast cancer risks associated
with carrying two mutations because this information may be informative
for genetic counselors and may provide clues to the carcinogenic
process.
Experimental Design: We genotyped 7,782 Polish breast cancer patients
and 6,233 controls for seven founder mutations in BRCA1 and
CHEK2.
Results: Of the 7,782 women with breast cancer, 1091 had one mutation
(14.0%) and 37 had two mutations (0.5%). Compared to controls,
the odds ratio for a BRCA1 mutation in isolation was 13.1 (95% CI 8.2
to 21). The odds ratio was smaller for BRCA1 mutation carriers who
also carried a CHEK2 mutation (OR = 6.6; 95% CI 1.5 to 29), but the
difference was not statistically significant. In contrast, the odds ratio for
women who carried two CHEK2 mutations (OR = 3.9; 95% CI 1.5 to
10) was greater than that for women who carried one CHEK2 mutation
(OR = 1.9; 95% CI 1.6 to 2.1). The odds ratio for women who carried
both a truncating mutation and the missense mutation in CHEK2 was
7.0 (95% CI 0.9 to 56) and was greater than for women who carried
the truncating mutation alone (OR = 3.3; 95% CI 2.4 to 4.3) or the missense
mutation alone (OR = 1.6; 95% CI 1.4-1.9).
Conclusion: Our study suggests that the risk of breast cancer in carriers
of a deleterious CHEK2 mutation is increased if the second allele
is the I157T missense variant.
P06.115
Preliminary genetic investigation of high-risk breast cancer
patients in Armenia
D. T. Babikyan, T. F. Sarkisian;
Center of Medical Genetics and Primary Health Care, Yerevan, Armenia.
Mutations in high-penetrance genes BRCA1 and BRCA2 are associated
with greater risk for developing breast cancer (BC). The benefit
from prevention is not only increased by early detection of BRCA mutations
in cases with strong family history, but also in early onset cases
who make up a large fraction of all BC cases. This is the first report
on preliminary results of high-risk BC cases in Armenia where the incidence
of the disease is the highest in the South Caucasian region. In
2008, BC cases with family history or with early onset of the disease
(before age 40 y.o.) consisted 6.3% and 25%, respectively, of all BC
cases, with an increasing incidence of the latter during last two decades.
In our pilot study we recruited 46 high risk BC cases (18 familial
cases, 3 breast and ovarian cancer cases, 5 bilateral cases, and 20
early onset cases).
Using SSCP screening method, we have found 2 BRCA1 missense
substitutions in 2 patients (Q356R, S694L) and one synonymous
BRCA1 polymorphism in other 2 patients (L771L). This is the first
report of S694V variant previously not reported in other populations
in contrast to Q356R and L771L. It is notable that all carriers of the
BRCA1 changes were early onset cases with no family history of BC.
Despite the lack of high sensitivity of the screening assay, the results
indicate a proportion of early onset BC cases with BRCA mutations
and the need to include them in the genetic counseling and mutations
screening procedure.