Search Results - EGA European Genome-Phenome Archive

OA_hip-G-1

Genotyping of hip osteoarthritis patients who have undergone total joint replacement

Dataset EGAD00010001292

Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing

Dataset EGAD00001000856

HipSci - Monogenic Diabetes - RNA Sequencing - July 2017

Dataset EGAD00001003530

HipSci - Monogenic Diabetes - RNA Sequencing - October 2016

Dataset EGAD00001003180

20180208_EGA_Trench_MetCellLine.1

Illumina platform sequencing data of SureSelect exome libraries prepared from 3 samples from one donor: a normal, primary breast cancer, and cell line derived from metastasis

Dataset EGAD00001003956

SF12374

SF12374 snATAC Oligodendroglioma. Tumor Location: Right frontal. Age: 33. Sex: Male.

Dataset EGAD00001006315

Reference epigenome Pancreas-Islet06 miRNA-Seq data generated from KEP study

Pancreas-Islet06 miRNA-Seq single end data

Dataset EGAD00001007187

Reference epigenome Pancreas-Islet07 miRNA-Seq data generated from KEP study

Pancreas-Islet07 miRNA-Seq single end data

Dataset EGAD00001007188

Reference epigenome Pancreas-Islet08 miRNA-Seq data generated from KEP study

Pancreas-Islet08 miRNA-Seq single end data

Dataset EGAD00001007189

Reference epigenome Fat-adipocyte03 miRNA-Seq data generated from KEP study

Fat-adipocyte03 miRNA-Seq single end data

Dataset EGAD00001007190

Reference epigenome Fat-adipocyte04 miRNA-Seq data generated from KEP study

Fat-adipocyte04 miRNA-Seq single end data

Dataset EGAD00001007191

Reference epigenome Fat-adipocyte05 miRNA-Seq data generated from KEP study

Fat-adipocyte05 miRNA-Seq single end data

Dataset EGAD00001007192

Reference epigenome Islet-derived_MSC08 mRNA-Seq data generated from KEP study

Islet-derived_MSC08 mRNA-Seq paired end data

Dataset EGAD00001007879

Reference epigenome Islet-derived_iPSC04 mRNA-Seq data generated from KEP study

Islet-derived_iPSC04 mRNA-Seq paired end data

Dataset EGAD00001007880

Reference epigenome Islet-derived_MSC06 miRNA-Seq data generated from KEP study

Islet-derived_MSC06 miRNA-Seq single end data

Dataset EGAD00001007881

Reference epigenome Islet-derived_MSC08 miRNA-Seq data generated from KEP study

Islet-derived_MSC08 miRNA-Seq single end data

Dataset EGAD00001007882

Reference epigenome Islet-derived_iPSC04 miRNA-Seq data generated from KEP study

Islet-derived_iPSC04 miRNA-Seq single end data

Dataset EGAD00001007883

Covacta OLINK QC metrics

Olink Explore 1536 dataset from serum of patients enrolled in the COVACTA trial. This dataset includes QC warning flag provided by Olink.

Dataset EGAD00001011167

Dental Caries: Whole Genome Association and Gene x Environment Studies

Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. Although overall caries prevalence has declined over the last 40 years, dental caries in the primary dentition and mean caries rates in children ages 2-11 has increased markedly over the past 12 years. Childhood caries is a serious public health issue because of associated health problems and because disparities in oral health have led to substantially higher average disease prevalence among children in poverty and in under-served racial and ethnic groups. These issues are of such concern that in 2005, the American Academy of Pediatrics made children's oral health one of their top areas of focus, as it is for the majority of the NIDCR "Disparities Centers". The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. Despite the strong evidence of a genetic component to risk for dental caries, there have been only a few studies of candidate genes in caries, and no published genome-wide scans. A comprehensive genome wide search is the only approach that will allow us to identify those genetic regions likely to harbor genes increasing the risk for dental caries, and eventually to identify the etiologic genes and to explore the interaction of those genes with microbiological, dietary, fluoride, and behavioral factors that are known to be associated with caries risk and progression. Therefore, the goal of this study is to perform genome-wide association (GWA) studies of dental caries with a large panel of SNP's (610,000) in families and individuals ascertained through multiple US sites (University of Pittsburgh and University of Iowa). The v2 release of this study includes 96 additional individuals who were genotyped with the CCDG: Dental Caries and CL/P in Guatemala project (dbGaP accession number phs000440) to augment the data initially presented here. These subjects were genotyped on the Illumina 610 platform to make their data comparable. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to dental caries through large-scale genome-wide association studies of well-characterized families and individuals at multiple sites in the U.S. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Samples of some participants in this study were selected for further genomic analysis. These results will be available in the dbGaP CIDR study: Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease (phs001591).

Study phs000095

Risk Assessment of Cerebrovascular Events (RACE) Study

This study includes 1,220 cases with young onset stroke (stroke before age 60 years) who are participants of the larger RACE study. Risk Assessment of Cerebrovascular Events (RACE) is an on-going existing case-control study of stroke now involving over 5000 imaging confirmed cases of stroke and 5000 controls, recruited from seven centers in Pakistan. The study is aimed to investigate the genetic, biomarker and lifestyle determinants of stroke and its subtypes. Cases are eligible for inclusion in the study if they: (i) are aged at least 18 years; (ii) present with a sudden onset of neurological deficit respecting a vascular territory with sustained deficit at 24 hours verified by medical attention within 72 hours after onset (onset is defined by when the patient was last seen normal and not when found with deficit); and (iii) the diagnosis is supported by CT/MRI; and (iv) present with a Modified Rankin Score < 2 prior to the stroke. Findings from patient's history, 12-lead ECG and CT or MRI of the brain. The mandatory procedures for inclusion in this investigation are: (i) clinical verification of cerebrovascular event within 72 hours of onset; (ii) neuroimaging CT (non-contrast) or MRI (MRI is not a mandatory investigation but recorded whenever ordered by the attending physician); and (iii) 12-lead ECG. All other ancillary investigations ordered by the attending physician are recorded as well. The TOAST classification method is used to classify ischemic stroke based on aetiology whereas the Oxfordshire classification is used to classify stroke neuro-anatomically. Control participants for this subset of young onset stroke were individuals enrolled in the Pakistan Risk of Myocardial Infarction Study (PROMIS), a case-control study of acute MI based in Pakistan. RACE capitalizes on the genetic data (including information on GWAS) that has already been collected from the healthy participants enrolled in PROMIS. RACE and PROMIS share similar methodology of recruitment. Participants from both these investigations are derived from similar catchment areas, hence providing an attractive opportunity for RACE to utilize PROMIS controls as common controls for genetic investigations. Controls in PROMIS were recruited following procedures and inclusion criteria as adopted for RACE cases. In order to minimize any potential selection biases, PROMIS controls selected for this stroke substudy were frequency matched to RACE cases based on age and gender and were recruited in the following order of priority: (1) non-blood related or blood related visitors of patients of the out-patient department; (2) non-blood related visitors of stroke patients; (3) patients of the out-patient department presenting with minor complaints (e.g. back pain, minor gastric complaints). Control subjects from the PROMIS study were genotyped at the Wellcome Trust Sanger Institute on the Illumina 660W Quad array. The Center for Non-Communicable Diseases, Pakistan, serves as the coordinating center for both RACE and PROMIS. More information on these research investigations can be found at www.cncdpk.com. This young onset stroke component to the RACE study was funded through the Gene Environment Association Studies initiative (GENEVA, www.genevastudy.org as one of three studies designed to assess the genetics of young onset stroke and modification of genetic effects by smoking. GENEVA is part of the trans-NIH Genes, Environment, and Health Initiative (GEI). Genotyping of 1,220 young onset stroke cases was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of cases and controls recruited within Pakistan. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000456

CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

Study phs001163

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Rotenone from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008052

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Resveratrol from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008050

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D1, replicate 2, glucose concentration 1mM

Dataset EGAD00001008046

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008044

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Rotenone from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008042

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Resveratrol from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008040

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008054

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D2, replicate 2, glucose concentration 1mM

Dataset EGAD00001008056

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Resveratrol from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008060

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Rotenone from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008062

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008064

Transcriptome of human CD4+ T-lymphyocyte (memory-T-cells) treated with Oligomycin from donor D3, replicate 2, glucose concentration 1mM

Dataset EGAD00001008066

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Resveratrol from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008076

Transcriptome of human CD4+ T-lymphyocyte (regulatory-T-cells) treated with Resveratrol from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008074

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Oligomycin from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008088

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Rotenone from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008090

Transcriptome of human CD4+ T-lymphyocyte (regulatory-T-cells) treated with Resveratrol from donor D3, replicate 2, glucose concentration 5mM

Dataset EGAD00001008078

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Oligomycin from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008080

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Rotenone from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008082

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Oligomycin from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008084

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Rotenone from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008086

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Resveratrol from donor D2, replicate 2, glucose concentration 5mM

Dataset EGAD00001008072

Transcriptome of human CD4+ T-lymphyocyte (regulatory-T-cells) treated with Resveratrol from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008070

Transcriptome of human CD4+ T-lymphyocyte (naive-T-cells) treated with Resveratrol from donor D1, replicate 2, glucose concentration 5mM

Dataset EGAD00001008068

McGill EMC Release 4 in tissue "Brodmann (1909) area 11"

Dataset EGAD00001001284

McGill EMC Release 4 in tissue "Brodmann (1909) area 44"

Dataset EGAD00001001285

input

Input dataset of human islets. To be used in conjuction with Cohesin and Mediator ChIP-Seq datasets.

Dataset EGAD00001005209

RNAseq sample

RNAseq sample used in study titled "Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy".

Dataset EGAD00001005747

Reference epigenome Islet-derived-MSC01 WGBS data generated from KEP study

Islet-derived-MSC01 WGBS paired end data

Dataset EGAD00001007140

Reference epigenome Islet-derived-MSC02 WGBS data generated from KEP study

Islet-derived-MSC02 WGBS paired end data

Dataset EGAD00001007141

Reference epigenome Islet-derived-MSC03 WGBS data generated from KEP study

Islet-derived-MSC03 WGBS paired end data

Dataset EGAD00001007142

Reference epigenome Islet-derived-MSC04 WGBS data generated from KEP study

Islet-derived-MSC04 WGBS paired end data

Dataset EGAD00001007143

Reference epigenome Islet-derived-iPSC01 WGBS data generated from KEP study

Islet-derived-iPSC01 WGBS paired end data

Dataset EGAD00001007144

Reference epigenome Islet-derived-iPSC02 WGBS data generated from KEP study

Islet-derived-iPSC02 WGBS paired end data

Dataset EGAD00001007145

Reference epigenome Fat-adipocyte03 mRNA-Seq data generated from KEP study

Fat-adipocyte03 mRNA-Seq paired end data

Dataset EGAD00001007157

Reference epigenome Fat-adipocyte04 mRNA-Seq data generated from KEP study

Fat-adipocyte04 mRNA-Seq paired end data

Dataset EGAD00001007158

Reference epigenome Fat-adipocyte05 mRNA-Seq data generated from KEP study

Fat-adipocyte05 mRNA-Seq paired end data

Dataset EGAD00001007159

Reference epigenome Pancreas-Islet06 mRNA-Seq data generated from KEP study

Pancreas-Islet06 mRNA-Seq paired end data

Dataset EGAD00001007166

Reference epigenome Pancreas-Islet07 mRNA-Seq data generated from KEP study

Pancreas-Islet07 mRNA-Seq paired end data

Dataset EGAD00001007167

Reference epigenome Pancreas-Islet08 mRNA-Seq data generated from KEP study

Pancreas-Islet08 mRNA-Seq paired end data

Dataset EGAD00001007168

Reference epigenome SMC01 h3k4me3 ChIP-Seq data generated from KEP study

SMC01 h3k4me3 ChIP-Seq paired end data

Dataset EGAD00001007311

Reference epigenome SMC05 h3k9me3 ChIP-Seq data generated from KEP study

SMC05 h3k9me3 ChIP-Seq paired end data

Dataset EGAD00001007336

Reference epigenome ADMSC05 h3k27me3 ChIP-Seq data generated from KEP study

ADMSC05 h3k27me3 ChIP-Seq paired end data

Dataset EGAD00001007375

Reference epigenome Islet-derived_MSC06 mRNA-Seq data generated from KEP study

Islet-derived_MSC06 mRNA-Seq paired end data

Dataset EGAD00001007878

CTCF-ChIP-Seq of cohesin-mutated and wildtype adult AMLs

ChIP-Seq targeting CTCF in cohesin-mutated (STAG2 or RAD21 mutations) and wildtype adult AMLs (CTRL-AMLs).

Dataset EGAD00001011200

Using Genomics to Reduce Breast Cancer Disparities in the African Diaspora

Differences in breast cancer incidence and mortality rates between North American Caucasian and African American women are well-described and transcend socioeconomic issues. Black women are diagnosed with breast cancer at a younger median age; have more clinically aggressive disease and stage-for-stage; and have higher mortality rates than age-matched Caucasian women. Black women in West Africa, the origin of the slave trade in the US in the 19th century and thus the founder population for most African Americans, have even higher rates of early-onset, poor-prognosis breast cancer than African American women. Racial difference in the distribution of intrinsic molecular subtypes has been well characterized in the US and throughout the African Diaspora as well. Despite the large efforts on characterizing racial/ethnic differences, however, the reasons women of African ancestry are disproportionately affected by breast cancer incidence and mortality remain poorly understood - largely due to paucity of data on inherent genomic differences that contribute to the disparities in incidence and progression of breast cancer across populations. West Africa Breast Cancer Study (WABCS) is an initiative that aims to comprehensively understand the genetic architecture of breast cancer in West Africans, the founder population of a large proportion of black women in the United States. The objective of the study was to provide a better understanding of the molecular genetic factors that influence prognosis in Nigerian breast cancer patients, and determine which of these alterations may be amenable to available therapy. To that end, we examined the molecular features of breast cancers of indigenous African women using a combination of whole-genome, whole-exome, and transcriptome sequencing (WGS, WES, and RNA-seq) on 194 tumors from Nigerian patients. The goal of this project was to obtain answers to two related research questions using an unscreened population without genetic admixture in Nigeria: 1) why are women of African ancestry more likely to develop aggressive young onset breast cancer? 2) What are the associated genomic and non-genomic risk factors? We hypothesize that the genomic determinants of breast cancer molecular subtypes in women of African ancestry are also molecular drivers of tumor progression and represent targets for interventions to improve clinical outcomes and close the mortality gap. By identifying causal links between genetic variants that promote aggressive tumor progression in Nigerian women in comparison to women from different population found in TCGA and ICGC, the present dataset will have significant public health impact on millions of women in the African Diaspora. The potential to identify novel pathways for interventions to reduce the increasing mortality gap between women of African and European ancestry is huge

Study phs001687

Cryptococcosis in Previously Healthy Adults

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors.

Study phs003871

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

Study EGAS00001008059

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