scholarly journals Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3015 ◽  
Author(s):  
George A. R. Wiggins ◽  
Logan C. Walker ◽  
John F. Pearson
Keyword(s):  
Gene Expression ◽  
Genetic Testing ◽  
Expression Profiles ◽  
Pathogenic Variant ◽  
Individual Risk ◽  
Cancer Genetic ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
The Impact

Germline pathogenic variants in BRCA1 and BRCA2 increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1 and BRCA2 pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of BRCA1 and BRCA2 variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic BRCA1 and BRCA2 variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from BRCA1 and BRCA2 pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.

scholarly journals Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260852
Author(s):  
Meryem Ozgencil ◽  
Julian Barwell ◽  
Marc Tischkowitz ◽  
Louise Izatt ◽  
Ian Kesterton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Ips Cells ◽  
Variants Of Uncertain Significance ◽  
Cellular Models ◽  
Pathogenic Variants ◽  
Damage Repair ◽  
Uncertain Significance ◽  
Induced Pluripotent ◽  
The Impact

Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

scholarly journals Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Ben Holmes ◽  
Seung Ho Jung ◽  
Jing Lu ◽  
Jessica A. Wagner ◽  
Liudmilla Rubbi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Current Intensity ◽  
Beneficial Effects ◽  
Group A ◽  
The Impact

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied.

Genetic Testing for Women Previously Diagnosed with Breast/Ovarian Cancer: Examining the Impact of BRCA1 and BRCA2 Mutation Searching

2002 ◽  
Vol 6 (2) ◽  
pp. 79-87 ◽  
Author(s):  
N. Hallowell ◽  
C. Foster ◽  
A. Ardern-Jones ◽  
R. Eeles ◽  
V. Murday ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Brca2 Mutation ◽  
Brca1 And Brca2 ◽  
The Impact

Downstream Revenue Generated by a Cancer Genetic Counselor

2021 ◽  
pp. OP.20.00464 ◽  
Author(s):  
Caitlin B. Mauer ◽  
Brian D. Reys ◽  
Reece E. Hall ◽  
Connor L. Campbell ◽  
Sara M. Pirzadeh-Miller
Keyword(s):  
Genetic Counseling ◽  
Cancer Genetics ◽  
Healthcare Systems ◽  
Pathogenic Variant ◽  
Full Time ◽  
Cancer Genetic ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Relative Value ◽  
Management Recommendations

QUESTION ASKED: How much downstream revenue do cancer genetic counselors (GCs) generate when they identify patients with hereditary breast and ovarian cancer (HBOC) ( BRCA1/BRCA2) and Lynch syndrome (LS) pathogenic variants? SUMMARY ANSWER: Over a 10-year period, the downstream revenue generated from cancer GCs’ identification of patients with HBOC and LS was $32.79 million in US dollars (USD) (mean/year = $3.25 million USD and mean/patient = $77,000 USD). One full-time GC would generate $1.49-$1.86 million USD in revenue per year ($1.26-$1.58 million USD for HBOC-positive patients and $227-$284,000 USD for LS-positive patients per year). WHAT WE DID: Expected reimbursement and work relative value units (wRVUs) were collected from all hospital and ambulatory or outpatient encounters for patients with HBOC or LS identified in the Cancer Genetics clinic. Total revenue was calculated for each patient after they met with a GC; patients were stratified into categories of affected or unaffected status and new or established patients in the hospital system. WHAT WE FOUND: The downstream revenue generated from 425 patients with HBOC or LS mutations totaled $32,798,000 USD and 73,957 work relative value units after their cancer genetics appointments. Patients unaffected with cancer (n = 176) generated $8,453,000 USD, whereas naïve patients (n = 96), defined as those whose first visit to the institution was for a genetic counseling consultation, generated $5,933,000 USD. BIAS, CONFOUNDING FACTOR(S): This study solely focuses on revenue generated from patients with HBOC or LS. However, with the advent of next-generation sequencing panels, many pathogenic variants are being identified in other genes, resulting in enhanced management recommendations. Therefore, the revenue brought in by a GC likely surpasses the data provided here. Additionally, these data focus strictly on downstream revenue generated from patients receiving follow-up care at our institution. Patient adherence to compliance of management recommendations can affect the overall amount of revenue generated. REAL-LIFE IMPLICATIONS: To our knowledge, this is the first study to describe the amount of revenue generated for an institution downstream of the identification of pathogenic variant carriers in cancer susceptibility genes by a GC. These data will aid healthcare systems and oncology practices in determining if there is standalone fiscal value to the downstream effect of genetic counseling services or if services need to be supplemented through other avenues. By identifying clinic demographics and volumes, test uptake rate, and positive pathogenic variant rate, cancer GCs and healthcare systems or oncology practices can determine the expected revenue generated from HBOC and LS pathogenic variant carriers at their own institution to justify positions and growth of their genetic counseling departments ( Fig. 1 ).

scholarly journals Anesthesia-Sepsis-Associated Alterations in Liver Gene Expression Profiles and Mitochondrial Oxidative Phosphorylation Complexes

2020 ◽  
Vol 7 ◽  
Author(s):  
Hari Prasad Osuru ◽  
Umadevi Paila ◽  
Keita Ikeda ◽  
Zhiyi Zuo ◽  
Robert H. Thiele
Keyword(s):  
Gene Expression ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Electron Transport Chain ◽  
Expression Profiles ◽  
Volatile Anesthetic ◽  
Heme Oxygenase 1 ◽  
Complex Ii ◽  
Transport Chain ◽  
The Impact

Background: Hepatic dysfunction plays a major role in adverse outcomes in sepsis. Volatile anesthetic agents may protect against organ dysfunction in the setting of critical illness and infection. The goal of this study was to study the impact of Sepsis-inflammation on hepatic subcellular energetics in animals anesthetized with both Propofol (intravenous anesthetic agent and GABA agonist) and Isoflurane (volatile anesthetic i.e., VAA).Methods: Sprague-Dawley rats were anesthetized with Propofol or isoflurane. Rats in each group were randomized to celiotomy and closure (control) or cecal ligation and puncture “CLP” (Sepsis-inflammation) for 8 h.Results: Inflammation led to upregulation in hepatic hypoxia-inducible factor-1 in both groups. Rats anesthetized with isoflurane also exhibited increases in bcl-2, inducible nitric oxide synthase, and heme oxygenase-1(HO-1) during inflammation, whereas rats anesthetized with Propofol did not. In rats anesthetized with isoflurane, decreased mRNA, protein (Complex II, IV, V), and activity levels (Complex II/III,IV,V) were identified for all components of the electron transport chain, leading to a decrease in mitochondrial ATP. In contrast, in rats anesthetized with Propofol, these changes were not identified after exposure to inflammation. RNA-Seq and real-time quantitative PCR (qPCR) expression analysis identified a substantial difference between groups (isoflurane vs. Propofol) in mitogen-activated protein kinase (MAPK) related gene expression following exposure to Sepsis-inflammation.Conclusions: Compared to rats anesthetized with Propofol, those anesthetized with isoflurane exhibit more oxidative stress, decreased oxidative phosphorylation protein expression, and electron transport chain activity and increased expression of organ-protective proteins.

scholarly journals RNAseq Studies Reveal Distinct Transcriptional Response to Vitamin a (VA) Deficiency in Small Intestine (SI) versus Colon, Discovering Novel VA-regulated Genes (P15-002-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Zhi Chai ◽  
Yafei Lyu ◽  
Qiuyan Chen ◽  
Cheng-Hsin Wei ◽  
Lindsay Snyder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Intestine ◽  
Vitamin A ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Differentially Expressed Gene ◽  
Gene Expression Profiles ◽  
Illumina Hiseq ◽  
The Impact

Abstract Objectives To characterize and compare the impact of vitamin A (VA) deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. Methods vitamin A deficient (VAD) mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. Total mRNA extracted from SI and colon were sequenced using Illumina HiSeq 2500 platform. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression patterns and co-expression patterns. Results The comparison between vitamin A sufficient (VAS) and VAD groups detected 49 and 94 DEGs in SI and colon, respectively. According to GO information, DEGs in the SI demonstrated significant enrichment in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, such as “humoral immune response” and “complement activation,” were positively associated with VA in SI. On the contrary, in colon, “cell division” was the only enriched category and was negatively associated with VA. WGCNA identified modules significantly correlated with VA status in SI and in colon. One of those modules contained five known retinoic acid targets. Therefore we have prioritized the other module members (e.g., Mbl2, Mmp9, Mmp13, Cxcl14 and Pkd1l2) to be investigated as candidate genes regulated by VA. Comparison of co-expression modules between SI and colon indicated distinct VA effects on these two organs. Conclusions The results show that VA deficiency alters the gene expression profiles in SI and colon quite differently. Some immune-related genes (Mbl2, Mmp9, Mmp13, Cxcl14 and Pkd1l2) may be novel targets under the control of VA in SI. Funding Sources NIH training grant and NIH research grant. Supporting Tables, Images and/or Graphs

scholarly journals Effect of apple food matrix on plasma flavan-3-ols distribution and nutrigenomic profile in response to a nutritional challenge in minipigs

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Laurent-Emmanuel Monfoulet ◽  
Caroline Buffiere ◽  
Geoffrey Istas ◽  
Claire Dufour ◽  
Carine le Bourvelec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Food Matrix ◽  
High Fat ◽  
Significant Difference ◽  
Nutritional Studies ◽  
The Impact ◽  
Apple Puree ◽  
Fat Meal ◽  
Apple Purée

AbstractFood matrix is known to interact with some dietary constituents and microconstituents during digestion. These interactions may potentially affect the metabolism and bioavailability of some compounds, and as a consequence modulate their biological effects. In this context, the aim of this study was to determine the effect of apple food matrix on the bioavailability of flavan-3-ols and on the ability of these compounds to modulate the nutrigenomic response to a high fat challenge in minipigs.Adult male Yucatan minipigs (n = 5) were assigned to a random treatment sequence of high-fat meals non supplemented or supplemented with 250 g of raw apple, 250 g of apple puree or 1.4 g of apple polyphenols extract, with a 7-days washout period between each treatment. Each supplementation provided 155 mg flavan-3-ol monomers. At each treatment period, fasting- and 1h-, 2h-, 3h-postprandial blood samples were collected, and the concentration in flavan-3-ol monomers was measured on hydrolyzed serum, using UPLC-Q-TOF MS. The ability of apple-derived products to modulate the postprandial gene expression profile was assessed and compared in circulating PBMCs collected at 3 h after consumption of the four tested meals using a microarray analysis.Results show that the apple matrix did not affect the kinetic of the postprandial absorption of flavan-3-ol monomers. The total flavan-3-ols concentrations measured at peak were significantly higher in the extract (x1.75), suggesting an impact of the apple matrix on flavan-3-ols absorption. However, no significant difference in total flavanols was observed between raw apple and apple puree.Principal Component Analysis of the microarray data from PBMCs identified three distinct clusters of gene expression patterns: one corresponding to gene expression profiles after the high-fat meal, one for meal supplemented with raw apples or apple puree, and a third cluster for meal supplemented with polyphenol extract. A set of 309 genes was identified as differentially expressed by apple-derived products compared to high-fat meal alone, including 93 modulated with the three apple products. The variations in gene expression were similar for only 75% of the 93 genes, suggesting that the apple matrix affects the nutrigenomic response to flavan-3-ols. A bioinformatics analysis revealed that genes affected by apple-derived products are involved in inflammation and leukocyte transendothelial migration, suggesting a beneficial impact of apple-derived products.In conclusion, these results raise awareness for considering the impact of food matrix on the biological responsiveness of polyphenols in future nutritional studies.

Gene Expression Profiles of Early Implant Adherent Cells in Smokers and Nonsmokers

2015 ◽  
Vol 41 (6) ◽  
pp. 640-645 ◽  
Author(s):  
Ghadeer Thalji ◽  
Lyndon F. Cooper ◽  
Salvador Nares
Keyword(s):  
Gene Expression ◽  
Early Stage ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Whole Genome ◽  
Adherent Cells ◽  
Mini Implants ◽  
Molecular Events ◽  
The Impact

The objective of this study was to evaluate the impact of smoking on the early molecular events involved in peri-implant healing at either a micro-roughened or a micro-roughened with superimposed nanofeatures surface implant in humans. Twenty-one subjects, 10 smokers and 11 nonsmokers received 4 mini-implants (2.2 × 5.0 mm; 2 of each surface). After 3 and 7 days, paired mini-implants were retrieved by reverse threading and RNA isolated from implant adherent cells. Whole genome microarrays were used interrogate the gene expression profiles. The study failed to identify differences in the gene expression profiles of implant adherent cells at this early stage of osseointegration (up to day 7) comparing smoker and nonsmoker individuals.

Spatial sampling approach to unravel the impact of soil texture and root genotype on maize root gene expression profiles

2020 ◽  
Author(s):  
Minh Ganther ◽  
Marie-Lara Bouffaud ◽  
Lucie Gebauer ◽  
François Buscot ◽  
Doris Vetterlein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soil Texture ◽  
Expression Profiles ◽  
Soil Column ◽  
Column Experiment ◽  
Spatial Sampling ◽  
Marker Genes ◽  
Sampling Depth ◽  
Plant Growth Hormones ◽  
The Impact

<p>The complex interactions between plant roots and soil microbes enable a range of beneficial functions such as nutrient acquisition, defense against pathogens and production of plant growth hormones. The role of soil type and plant genotype in shaping rhizosphere communities has been explored in the past, but often without spatial context. The spatial resolution of rhizosphere processes enables us to observe pattern formation in the rhizosphere and investigate how spatial soil organization is shaped through soil–plant–microbiome interactions.</p><p>We applied spatial sampling in a standardized soil column experiment with two maize genotypes (wildtype vs. <em>roothairless3</em>) and two different soil textures (loam vs. sand) in order to investigate how in particular functions of the maize roots relating to nutrient/water uptake, immunity/defense, stress and exudation are affected. RNA sequencing and differential gene expression analysis were used to dissect impact of soil texture, root genotype and sampling depth. Our results indicate that variance in gene expression is predominantly explained by soil texture as well as sampling depth, whereas genotype appears to play a less pronounced role at the analyzed depths. Gene Ontology enrichment analysis of differentially expressed genes between soil textures revealed several functional categories and pathways relating to phytohormone-mediated signaling, cell growth, secondary metabolism, and water homeostasis. Community analysis of rhizosphere derived ACC deaminase active (acdS gene including) plant beneficial bacteria, which suppress the phytohormone ethylene production, suggests that soil texture and column depth are the major factors that affect acdS community composition.</p><p>From the comprehensive gene expression analyses we aim to identify maize marker genes from the relevant core functional groups. These marker genes will be potentially useful for future experiments; such as field plot experiments for investigation of later-emerging plant properties.</p><p>This research was conducted within the research program “Rhizosphere Spatiotemporal Organisation – a Key to Rhizosphere Functions” of the German Science Foundation (TA 290/5-1).</p>

Interaction of Stem Cells and Their Niche: Behavior and Gene Expression Profiles of CD34+/CD38− Cells upon Co-Cultivation with AFT024.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1281-1281
Author(s):  
Wolfgang Wagner ◽  
Rainer Saffrich ◽  
Ute Wirkner ◽  
Volker Eckstein ◽  
Jonathon Blake ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Differential Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Nuclear Antigen ◽  
Cd34 Cells ◽  
Differential Gene ◽  
The Impact

Abstract Cell-cell contact between stem cells and cellular determinants of the microenvironment plays an essential role in the regulation of self-renewal and differentiation. The stromal cell line derived from murine fetal liver (AFT024) has been shown to support maintenance of primitive human hematopoietic progenitor cells (HPC) in vitro. We have studied the interaction between HPC (defined as CD34+/CD38− umbilical cord blood cells) and AFT024 and the impact of co-cultivation on the behavior and gene expression of HPC. By time lapse microscopy the mobility and behavior of CD34+/CD38− cells were monitored. Approximately 30% of the CD34+/CD38− cells adhered to the cellular niche through an uropod. CD44 and CD34 were co-localized at the site of contact. Gene expression profiles of CD34+/CD38− cells were then compared upon co-cultivation either with or without AFT024. After cultivation for 16h, 20h, 48h or 72h the HPC were separated form the feeder layer cells by a second FAC-Sort. Differential gene expression was analyzed using our Human Genome cDNA Microarray of over 51,145 ESTs. Among the genes with the highest up-regulation in contact with AFT024 were several genes involved in cell adhesion, proliferation and DNA-modification including tubulin genes, ezrin, complement component 1 q subcomponent 1 (C1QR1), proto-oncogene proteins c-fos and v-fos, proliferating cell nuclear antigen (PCNA), HLA-DR, gamma-glutamyl hydrolase (GGH), minichromosome maintenance deficient 6 (MCM6), uracil-DNA glycolase (UNG) and DNA-methyltransferase 1 (DNMT1). In contrast, genes that were down-regulated after contact with AFT024 included collagenase type iv (MMP2), elastin (ELN) and hemoglobin genes. Differential expression of six genes was confirmed by RT-PCR. Other authors have reported on the differential gene expression profiles of CD34+ cells derived from the bone marrow versus those from G-CSF mobilized blood. As CD34+ cells from the bone marrow might represent cells exposed to the natural HPC niche we have then compared our findings with these experiments. In these comparisons we identified several overlapping genes that are involved in regulation of cell cycle and DNA repair including PCNA, DNMT1, MCM6, MCM2, CDC28 protein kinase regulatory subunit 1B (CKS1B), Topoisomerase II (TOP2a), DNA Ligase 1 (LIG1) and DNA mismatch repair protein MLH1. All these genes were up-regulated among CD34+/CD38− cells upon co-culture with AFT024, as well as among CD34+ cells derived from the bone marrow versus those from peripheral blood. Our studies support the hypothesis that intimate contact and adhesive interaction of HPC with their niche profoundly influenced their proliferative potential and their differentiation program.

Sign in / Sign up

Export Citation Format

Share Document