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abstract
Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.
Germline
mutations in BRCA1 gene have been reported in up to 20 % of epithelial
ovarian cancer (EOC) patients. Distinct clinical characteristics have
been attributed to this special EOC population. We hypothesized that
mutations in different BRCA1 gene exons may differently affect the
clinical course of the disease. The aim of this study was to analyze, in
a large cohort of primary EOCs, the clinical impact of mutations in
BRCA1 gene exon 11, the largest exon of the gene sequence encoding the
60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients,
treated between 2000 and 2008 at Charité University Hospital of Berlin,
were included. Patients' blood samples were obtained from the Tumor
Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing
of BRCA1 gene exon 11 was performed for each patient to detect
mutations. Based on their BRCA1 exon 11 mutational status, patients were
compared regarding clinico-pathological variables and survival.
Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %).
Further 10/263 (3.8 %) cases showed variants of uncertain significance
(VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian
carcinomas (p = 0.05). Age at diagnosis was significantly younger in
Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis,
BRCA1 exon 11 mutational status was not found to be an independent
predictive factor for optimal cytoreduction, platinum response, or
survival. Mutations in BRCA1 gene exon 11 seem to predispose women to
exclusively develop a Type 2 ovarian cancer at younger age. Exon 11
BRCA1-mutated EOC patients showed distinct clinico-pathological features
but similar clinical outcome with respect to sporadic EOC patients.
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