Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives

<p>Abstract</p> <p>Background</p> <p>Women from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the <it>BRCA1/2 </it>genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons.</p> <p>Methods</p> <p>We conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive <it>BRCA1/2 </it>genetic diagnostic test (where no mutations or unclassified variants were identified). We arranged three focus groups for affected women and their close female relatives - 13 women took part. We also interviewed 12 health professionals who were involved in the care of these women.</p> <p>Results</p> <p>The majority of the women had a good grasp of the meaning of their own or a family member's inconclusive result, but a few indicated some misunderstanding. Most of the women in this study underwent the test for the benefit of others in the family and none mentioned that they were having the test purely for themselves. A difficult issue for sisters of affected women was whether or not to undertake prophylactic breast surgery. The professionals were sensitive to the difficulties in explaining an inconclusive result. Some felt frustrated that technology had not as yet provided them with a better tool for prediction of risk.</p> <p>Conclusions</p> <p>Some of the women were left with the dilemma of what decision to make regarding medical management of their cancer risk. For the most part, the professionals believed that the women should be supported in whatever management decisions they considered best, provided these decisions were based on a complete and accurate understanding of the genetic test that had taken place in the family.</p

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms

Определение скорости перемещения деформаций растяжений в массиве при подземной выемке угля

Приведена швидкість переміщення деформацій в непорушеному масиві. Встановлено, що швидкість в породах середнього ступеня метаморфізму складає 15 м/добу. Середня швидкість переміщення деформацій в сланцях – 10 м/добу, в піщаниках – 15 м/добу. При повторній підробці швидкість переміщення деформацій складає 17 м/добу.Deformation’s speed travel in the virgin rock massif is given in this article. It has been determined that deformation’s speed in the rocks of medium-scale metamorphism was 15 meters over the entire circadian period. The average speed of deformation’s travel in the shale rocks is 10 meters over the entire circadian period and in the sandstone is 15 meters over the entire circadian period. During the recurring undermining the speed travel of deformations is 17 meters over the entire circadian period

機能獲得性STAT1変異を有する慢性皮膚粘膜カンジダ症に対する迅速診断法

内容の要旨 , 審査の要旨広島大学(Hiroshima University)博士(医学)Philosophy in Medical Sciencedoctora

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

Caractérisation de la réponse immunitaire de l'épiderme grâce à l'étude de l'organisme modèle Caenorhabditis elegans

L'épiderme constitue la première ligne de défense d'un organisme. Pour ma thèse, j'ai utilisé le nématode Caenorhabditits elegans comme organisme modèle afin détudier la réponse immunitaire mise en place au sein de l'épiderme suite à l'infeection par le champignon nématophage Drechmeria coniospora. Ce champignon adhère à la cuticule du ver et pénètre via l'épiderme. Notre laboratoire a démontré que C. elegans produit des AMP (pour AntiMicrobial Peptides) de manière tissu spécifique, en réponse à l'inferction et suite à une blessure de l'épiderme. Afin de disséquer la réponse immunitaire conduisant à l'expression des AMP, des mutants nipi pour No Induction of Peptide after Infection ont été générés. Mon travail de thèse s'est focalisé sur le mutant nipi-3, qui de manière intéressante, bloque la production d'AMP suite à l'infection mais pas suite à la blessure. j'ai identifié par clonage positionnel la mutation responsable du phénotype dans le domaine kinase d'une sérine/théorine kinase présentant des homoloies avec la protéine hTRIBBLES-1. Par des études épistasiques j'ai pu déterminer la position de NIPI-3 par rapport aux acteurs impliqués dans la production des AMPS. Grâce à une approche de crible double hybride, j'ai identifié le facteur de transcription CEBP-1 comme potentiel partenaire de NIPI-3. une telle interaction est conservée chez les anthropodes et les mammifères. Par des études épistatiques j'ai pu attribuer à CEBP-1 un rôle inhibiteur dans la production des AMP. Les travaux que j'ai effectués pendant ma thèse ont contribué à identifier de nouveaux acteurs impliqués dans la réponse immunitaire du ver et à démontrer la complexité de cette réponseIn every organism, the epidermis constitute the first line of defense. For my PhD, I used the nematod Caenorhabditis elegans as a model organism to study the epidermal immune response following infection with the nematode specific funfus, Drechmeria coniospora. This fungus adhere to the cuticle of the worm and penetrate through the epidermis. Our la showed that C. elegans produces AntiMicrobial Peptides (AMP) within this tissu following infection and wounding. To decipher the mecanisms involved in this production mutant worms unable to produce AMP following infection were generated.The were called nipi for No Induction of Peptide after Infection. For my PhD, I focused on the nipi-3 mutant that, interestingly, inhibits AMPs production following infection but nor following wounding. I identified the mutation responsible for the phenotype as being encode in the kinase domain of a serine/threonine kinase that show homologies with hTRIBBLES-1. By epistasic studies, I determined the position of NIPI-3 in the immune signaling pathways leading to the AMPs production. Thanks to a yeast two hybrid screen, I identified the transcription factor CEBP-1 as a potential interactor of NIPI-3. Such a interaction has been describe in anthropods and mammals. I discovered that CEBP-1 acts as negative regulator of the AMPs production. My thesis work contributes to identify new components of the worm immune response and to highlight the complexity of this responseAIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF