Dataset Information

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma.

ABSTRACT:

Background

Adenosine-to-inosine (A-to-I) RNA editing is an essential post-transcriptional mechanism mediated by ADAR enzymes that have been recently associated with cancer.

Results

Here, we characterize the inosinome signature in normal brain and de novo glioblastoma (GBM) using new metrics that re-stratify GBM patients according to their editing profiles and indicate this post-transcriptional event as a possible molecular mechanism for sexual dimorphism in GBM. We find that over 85% of de novo GBMs carry a deletion involving the genomic locus of ADAR3, which is specifically expressed in the brain. By analyzing RNA editing and patient outcomes, an intriguing gender-dependent link appears, with high editing of Alus shown to be beneficial only in male patients. We propose an inosinome-based molecular stratification of GBM patients that identifies two different GBM subgroups, INO-1 and INO-2, which can identify novel high-risk gender-specific patient groups for which more aggressive treatments may be necessary.

Conclusions

Our data provide a detailed picture of RNA editing landscape in normal brain and GBM, exploring A-to-I RNA editing regulation, disclosing unexpected editing implications for GBM patient stratification and identification of gender-dependent high-risk patients, and suggesting COG3 I/V as an eligible site for future personalized targeted gene therapy.

SUBMITTER: Silvestris DA

PROVIDER: S-EPMC6373152 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma.

Silvestris Domenico Alessandro DA Picardi Ernesto E Cesarini Valeriana V Fosso Bruno B Mangraviti Nicolò N Massimi Luca L Martini Maurizio M Pesole Graziano G Locatelli Franco F Gallo Angela A

Genome biology 20190213 1

<h4>Background</h4>Adenosine-to-inosine (A-to-I) RNA editing is an essential post-transcriptional mechanism mediated by ADAR enzymes that have been recently associated with cancer.<h4>Results</h4>Here, we characterize the inosinome signature in normal brain and de novo glioblastoma (GBM) using new metrics that re-stratify GBM patients according to their editing profiles and indicate this post-transcriptional event as a possible molecular mechanism for sexual dimorphism in GBM. We find that over ...[more]

PMID: 30760294

Similar Datasets

Project description:BackgroundSubarachnoid hemorrhage (SAH) represents a severe stroke subtype. Our study aims to develop gender-specific prognostic prediction models derived from distinct prognostic factors observed among different-gender patients.MethodsInclusion comprised SAH-diagnosed patients from January 2014 to March 2016 in our institution. Collected data encompassed patients' demographics, admission severity, treatments, imaging findings, and complications. Three-month post-discharge prognoses were obtained via follow-ups. Analyses assessed gender-based differences in patient information. Key factors underwent subgroup analysis, followed by univariate and multivariate analyses to identify gender-specific prognostic factors and establish/validate gender-specific prognostic models.ResultsA total of 929 patients, with a median age of 57 (16) years, were analyzed; 372 (40%) were male, and 557 (60%) were female. Differences in age, smoking history, hypertension, aneurysm presence, and treatment interventions existed between genders (p < 0.01), yet no disparity in prognosis was noted. Subgroup analysis explored hypertension history, aneurysm presence, and treatment impact, revealing gender-specific variations in these factors' influence on the disease. Screening identified independent prognostic factors: age, SEBES score, admission GCS score, and complications for males; and age, admission GCS score, intraventricular hemorrhage, treatment interventions, symptomatic vasospasm, hydrocephalus, delayed cerebral ischemia, and seizures for females. Evaluation and validation of gender-specific models yielded an AUC of 0.916 (95% CI: 0.878-0.954) for males and 0.914 (95% CI: 0.885-0.944) for females in the ROC curve. Gender-specific prognostic models didn't significantly differ from the overall population-based model (model 3) but exhibited robust discriminative ability and clinical utility.ConclusionVariations in baseline and treatment-related factors among genders contribute partly to gender-based prognosis differences. Independent prognostic factors vary by gender. Gender-specific prognostic models exhibit favorable prognostic performance.

Project description:Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific differences in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, ∼450 k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with significantly higher monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific difference may reflect a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific difference in peripheral blood leukocyte composition that is detectable in methylomic profiles and that may reflect long-standing changes associated with PTSD diagnosis.

Project description:BACKGROUND: Cardiovascular disease (CVD) incidence, complications and burden differ markedly between women and men. Although there is variation in the distribution of lifestyle factors between the genders, they do not fully explain the differences in CVD incidence and suggest the existence of gender-specific genetic risk factors. We aimed to estimate whether the genetic risk profiles of coronary heart disease (CHD), ischemic stroke and the composite end-point of CVD differ between the genders. METHODOLOGY/PRINCIPAL FINDINGS: We studied in two Finnish population cohorts, using the case-cohort design the association between common variation in 46 candidate genes and CHD, ischemic stroke, CVD, and CVD-related quantitative risk factors. We analyzed men and women jointly and also conducted genotype-gender interaction analysis. Several allelic variants conferred disease risk for men and women jointly, including rs1801020 in coagulation factor XII (HR = 1.31 (1.08-1.60) for CVD, uncorrected p = 0.006 multiplicative model). Variant rs11673407 in the fucosyltransferase 3 gene was strongly associated with waist/hip ratio (uncorrected p = 0.00005) in joint analysis. In interaction analysis we found statistical evidence of variant-gender interaction conferring risk of CHD and CVD: rs3742264 in the carboxypeptidase B2 gene, p(interaction) = 0.009 for CHD, and rs2774279 in the upstream stimulatory factor 1 gene, p(interaction) = 0.007 for CHD and CVD, showed strong association in women but not in men, while rs2069840 in interleukin 6 gene, p(interaction) = 0.004 for CVD, showed strong association in men but not in women (uncorrected p-values). Also, two variants in the selenoprotein S gene conferred risk for ischemic stroke in women, p(interaction) = 0.003 and 0.007. Importantly, we identified a larger number of gender-specific effects for women than for men. CONCLUSIONS/SIGNIFICANCE: A false discovery rate analysis suggests that we may expect half of the reported findings for combined gender analysis to be true positives, while at least third of the reported genotype-gender interaction results are true positives. The asymmetry in positive findings between the genders could imply that genetic risk loci for CVD are more readily detectable in women, while for men they are more confounded by environmental/lifestyle risk factors. The possible differences in genetic risk profiles between the genders should be addressed in more detail in genetic studies of CVD, and more focus on female CVD risk is also warranted in genome-wide association studies.

Dataset Information

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma.

Background

Results

Conclusions

Publications

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets