Guidelines for Disclosing Genetic Information to Family Members: from Development to Use

[À l'origine dans / Was originally part of : CRDP - Droit, biotechnologie et rapport au milieu

Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management

[CODE] VallejosGroup/CompRisksVignettes: Final code used in Monterrubio-Gomez et al (2024)

This is the final version of the code used to generate the results shown in Monterrubio-Gomez et al (2024), Biometrical JournalKarlaMonterrubio, Catalina Vallejos, & Nathan Constantine-Cooke. (2024). VallejosGroup/CompRisksVignettes: Final code used in Monterrubio-Gomez et al (2024) (Version biometricaljournal2024). Zenodo. https://doi.org/10.5281/zenodo.1055468

DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts

Epigenome-wide association studies (EWASs) of six metabolic traits were performed using whole-blood DNA methylation (DNAm) in Generation Scotland with N > 17,000 participants. The first set of EWAS models were adjusted for estimated white blood cells, and an epigenetic smoking score. The second set of EWAS models were further adjusted for the first 20 DNAm principal components. A total of 12 EWAS models were run (2 models per metabolic trait). Authors: Hannah M. Smith, Hong Kiat Ng, Joanna E. Moodie, Danni A. Gadd, Daniel L. McCartney, Elena Bernabeu, Archie Campbell, Paul Redmond, Adele Taylor, Danielle Page, Janie Corley, Sarah E. Harris, Darwin Tay, Ian J. Deary, Kathryn L. Evans, Matthew R. Robinson, John C. Chambers, Marie Loh, Simon R. Cox, Riccardo E. Marioni, Robert F. Hillary medRxiv 2024.05.29.24308103 Contact: Riccardo E. Marioni, [email protected], R. (2024). DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts [Data set]. Zenodo. https://doi.org/10.5281/zenodo.1399883

Bridging-induced phase separation and loop extrusion drive noise in chromatin transcription

Cell-to-cell heterogeneity in transcription, or transcriptional noise, is important in cellular development and in disease. The molecular mechanisms driving it are, however, elusive and ill-understood. Here, we use computer simulations to explore the role of 3D chromatin structure in driving transcriptional noise. We study a simple polymer model where proteins – modeling complexes of transcription factors and polymerases – bind multivalently to transcription units – modeling regulatory elements such as promoters and enhancers. We also include cohesin-like factors which extrude chromatin loops that are important for the physiological folding of chromosomes. We find that transcription factor binding creates spatiotemporal patterning and a highly variable correlation time in transcriptional dynamics, which is linked to the cell-to-cell variation in gene expression. Loop extrusion also contributes to noise, as the stochastic nature of this process leads to different networks of cohesin loops in different cells in our simulations. Our results could be tested with single-cell experiments and provide a pathway to understanding the principles underlying transcriptional plasticity in vivo. This dataset contains the simulation code and supplemental simulation movies of the associated paper

Human tripartite motif protein 52 is required for cell context-dependent proliferation

Tripartite motif (TRIM) proteins have been shown to play important roles in cancer development and progression by modulating cell proliferation or resistance from cell death during non-homeostatic stress conditions found in tumor micro-environments. In this study, we set out to investigate the importance for cellular fitness of the virtually uncharacterized family member TRIM52. The human TRIM52 gene has arisen recently in evolution, making it unlikely that TRIM52 is required for basic cellular functions in normal cells. However, a recent genome-wide ablation screening study has suggested that TRIM52 may be essential for optimal proliferation or survival in certain genetic cancer backgrounds. Identifying genes which fit this concept of genetic context-dependent fitness in cancer cells is of interest as they are promising targets for tumor-specific therapy. We report here that TRIM52 ablation significantly diminished the proliferation of specific glioblastoma cell lines in cell culture and mouse xenografts by compromising their cell cycle progression in a p53-dependent manner. Together, our findings point to a non-redundant TRIM52 function that is required for optimal proliferation.Copyright: Benke et a

Bacteriophage-encoded toxins: the lambda-holin protein causes caspase-independent non-apoptotic cell death of eukaryotic cells

The bacteriophage-encoded holin proteins are known to promote bacterial cell lysis by forming lesions within the cytoplasmic membrane. Recently, we have shown that the bacteriophage lambda-holin protein exerts cytotoxic activity also in eukaryotic cells accounting for a reduced tumour growth in vivo. In order to elucidate the mechanisms of lambda-holin-induced mammalian cell death, detailed biochemical and morphological analyses were performed. Colocalization analyses by subcellular fractionation and organelle-specific fluorescence immunocytochemistry indicated the presence of the lambda-holin protein in the endoplasmic reticulum and in mitochondria. Functional studies using the mitochondria-specific fluorochrome JC-1 demonstrated a loss of mitochondrial transmembrane potential in response to lambda-holin expression. Morphologically, these cells exhibited unfragmented nuclei but severe cytoplasmic vacuolization representing signs of oncosis/necrosis rather than apoptosis. Consistently, Western blot analyses indicated neither an activation of effector caspases 3 and 7 nor cleavage of the respective substrate poly(ADP-ribose) polymerase (PARP) in an apoptosis-specific manner. These findings suggest that the lambda-holin protein mediates a caspase-independent non-apoptotic mode of cell death