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open access pdf (technical)
For the evaluation of our approach 127 ovarian tumour samples derived from 96 271 patients were tested: 29 with a BRCA1, 14 with a BRCA2 and 53 without a germline mutation 272 in either gene.
Histology review of the ovarian carcinomasabstract:
Histology revision by an expert pathologist revealed that 83% of the carcinomas derived from germline mutation carriers had a high grade serous histology (n=35). The other patients with a germline mutation in BRCA1 or BRCA2 presented carcinomas with a mixed (n=2), high grade endometrioid (n=1), clear cell (n=1) and poorly/undifferentiated (n=3) histology (Supp. Table S6a)......
Novel BRCA1 and BRCA2 Tumour Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas
With the recent introduction of
Poly(ADP-ribose) polymerase (PARP) inhibitors, a promising novel therapy
has become available for ovarian carcinoma patients with inactivating BRCA1 or BRCA2 mutations in their tumour. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2
in the tumour is required. For reliable evaluation of germline and
somatic mutations in these genes in DNA derived from formalin-fixed,
paraffin-embedded (FFPE) tissue, we have developed a single molecule
molecular inversion probe (smMIP)-based targeted next generation
sequencing (NGS) approach. Our smMIP-based NGS approach provides
analysis of both strands of the open-reading frame of BRCA1 and BRCA2,
enabling the discrimination between real variants and formalin induced
artefacts. The single molecule tag enables compilation of unique reads
leading to a high analytical sensitivity and enabling assessment of the
reliability of mutation-negative results. MLPA and MS-MLPA were used to
detect exon deletions of BRCA1 and methylation of the BRCA1
promoter, respectively. Here, we show that this combined approach
allows the rapid and reliable detection of both germline and somatic
aberrations affecting BRCA1 and BRCA2 in DNA derived
from FFPE ovarian carcinomas, enabling improved hereditary cancer risk
assessment and clinical treatment of ovarian cancer patients.
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