Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele

Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers

Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Interaction of 5-bromоmethylfurfural with Silver Fluoride in Methanol and Toluene

При взаимодействии 5-бромметилфурфурола и фторида серебра (I) в безводном толуоле и водно-метанольной среде при 25ºС образуется новое соединение, 5-фторметилфурфурол - продукт нуклеофильного замещения атома галогена. Его выход в водно-метанольной среде составляет 1-3 %, а в безводном толуоле - до 10 %. В качестве основных продуктов реакции образуются продукты алкилирования толуола и 5-гидроксиметилфурфурола метиленфурфурол-катионом.The action of silver (I) fluoride on the 5-bromоmethyfurfural leads to a new compound, 5-fluoromethylfurfural, as a product of nucleophilic substitution. Yields of 5-fluoromethylfurfural attain 10 % and 1-3 % in anhydrous toluene and water-methanol medium, respectively. Main products of the reaction are the products of toluene and 5-hydroxymethylfurural alkylation by methylenfurfuryl cation

Interaction of 5-bromоmethylfurfural with Silver Fluoride in Methanol and Toluene

При взаимодействии 5-бромметилфурфурола и фторида серебра (I) в безводном толуоле и водно-метанольной среде при 25ºС образуется новое соединение, 5-фторметилфурфурол - продукт нуклеофильного замещения атома галогена. Его выход в водно-метанольной среде составляет 1-3 %, а в безводном толуоле - до 10 %. В качестве основных продуктов реакции образуются продукты алкилирования толуола и 5-гидроксиметилфурфурола метиленфурфурол-катионом.The action of silver (I) fluoride on the 5-bromоmethyfurfural leads to a new compound, 5-fluoromethylfurfural, as a product of nucleophilic substitution. Yields of 5-fluoromethylfurfural attain 10 % and 1-3 % in anhydrous toluene and water-methanol medium, respectively. Main products of the reaction are the products of toluene and 5-hydroxymethylfurural alkylation by methylenfurfuryl cation

Role of the Transmembrane Potential in the Membrane Proton Leak

The molecular mechanism responsible for the regulation of the mitochondrial membrane proton conductance (G) is not clearly understood. This study investigates the role of the transmembrane potential (ΔΨm) using planar membranes, reconstituted with purified uncoupling proteins (UCP1 and UCP2) and/or unsaturated FA. We show that high ΔΨm (similar to ΔΨm in mitochondrial State IV) significantly activates the protonophoric function of UCPs in the presence of FA. The proton conductance increases nonlinearly with ΔΨm. The application of ΔΨm up to 220 mV leads to the overriding of the protein inhibition at a constant ATP concentration. Both, the exposure of FA-containing bilayers to high ΔΨm and the increase of FA membrane concentration bring about the significant exponential Gm increase, implying the contribution of FA in proton leak. Quantitative analysis of the energy barrier for the transport of FA anions in the presence and absence of protein suggests that FA− remain exposed to membrane lipids while crossing the UCP-containing membrane. We believe this study shows that UCPs and FA decrease ΔΨm more effectively if it is sufficiently high. Thus, the tight regulation of proton conductance and/or FA concentration by ΔΨm may be key in mitochondrial respiration and metabolism