UNASSIGNED: 561 Background: Mutations in @entity0 gene 1 and 2( @entity6069 ) account for 50% of the @entity5344 . About one third of the mutations are of unknown pathogenetic relevance (unclassified variants, UCV). We recently identified @entity24717 as a third high penetrance gene (Meindl et al., 2010). Like @entity6069 , @entity24717 is also involved in homologous recombination repair (HRR) in response to DNA double strand breaks. It has recently been shown that cells with @entity14183 are sensitive to synthetic lethality mediated by @entity9190 inhibition. Under the assumption that further high risk genes may exist which acts through the HRR pathway we aimed to develop a reliable functional test system which allows the evaluation of @entity14183 in heterozygous carriers. METHODS: We included eight carriers of a pathogenic @entity2674 mutation, two carriers of a pathogenic @entity24717 mutation and nine healthy controls as well as seven @entity2674 UCV carriers. @entity1 and control lymphocytes were y-irradiated in G2 phase to introduce DNA-DSB. For the assessment of HRR capacity, metaphase chromosomes were stained by multicolour fluorescence in situ hybridisation ( @entity24328 ). Chromosomal translocations and breakages were counted per mitosis and referred to total chromosomal number. The aberration frequency of @entity2674 and @entity24717 carriers versus the controls was compared. RESULTS: Lymphocytes from @entity2674 and @entity24717 pathogenic mutation carriers versus controls showed a mean aberration frequency of 2.51  0.36 (standard deviation, SD) and 2.7  0.25 (SD), respectively, versus 1.4  0.44 (SD) chromosomal aberrations per metaphase with no overlap (p-value <0.001; Student's t-test). Seven @entity1 carrying an UCV in @entity2674 could be allocated to either the pathogenic or the control group. CONCLUSIONS: Our test system allows the detection of @entity14183 in heterozygous lymphocytes of @entity2674 and @entity24717 gene mutation carriers and is currently evaluated in @entity5345 positive cases. The assay may enable the identification of @entity14183 irrespective of the underlying gene defect and may also serve as a biomarker for sensitivity to @entity9190 inhibition.

A functional assay for the identification of DNA double-strand break repair deficiency in heterozygous carriers of XXXX and @entity24717 mutations.

@entity1 :: ('9606', 'Species') :: ['patients', 'Patient'] @entity0 :: ('MESH:D001943', 'Disease') :: ['breast cancer'] @entity5344 :: ('MESH:D061325', 'Disease') :: ['familial aggregation of breast and ovarian cancer'] @entity24717 :: ('5889', 'Gene') :: ['RAD51C'] @entity5345 :: ('672', 'Gene') :: ['BRCA1'] @entity2674 :: ('675', 'Gene') :: ['BRCA2'] @entity24328 :: ('119488', 'Species') :: ['M-FISH'] @entity14183 :: ('MESH:D049914', 'Disease') :: ['HRR deficiency'] @entity6069 :: ('672;675', 'Gene') :: ['BRCA1/2'] @entity9190 :: ('1302', 'Gene') :: ['PARP']
@entity6069 :: (672;675,Gene) :: ['BRCA1/2']
