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• InTEAM Consortium - Alcoholic Hepatitis

  Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we describe the transcriptional programs involved in disease progression. We uncovered that development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). The PPARG predicted activation state was found increased in early forms of ALD, while AH was associated by a marked decrease in HNF4A-dependent gene expression along with a marked expression of the fetal HNF4A isoform (P2). TGFB1, a key upstream transcriptome regulator in AH, induced the use of HNF4a P2 promoter in hepatocytes, which resulted in abnormal bile acid synthesis and defective metabolic and synthetic functions. PPARG agonists partially prevented this effect. We conclude that targeting TGFB1 and epigenetic drivers that modulate HNF4A-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. The study was conducted thanks to a multicenter collaboration under the National Institute of Alcohol Abuse and Alcoholism (NIAAA)-funded consortium: Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTEAM).

  Study phs001807

• Tissue-specific mutation accumulation in human adult stem cells during life

  Gradual accumulation of mutations in human adult stem cells during life is associated with various age-related diseases, including cancer. The number of stem cell divisions throughout life is believed to be a major determinant for mutation accumulation and could explain the extreme variation of cancer incidence across different organs. Yet, mutation patterns and rates of healthy adult stem cells remain unknown. Here, we determined genome-wide mutation patterns in primary adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years. We find that the number of mutations increases linearly with age up to several thousand mutations per cell at 87 years of age, while mutation spectra remain constant throughout life. Small intestine and colon stem cells have a 2-fold higher mutation rate per year compared with liver stem cells. These differences could be exclusively attributed to the mutagenic action of spontaneous deamination of cytosine residues and may reflect the high stem cell division rate in these tissues. The genomic distribution of somatic mutations is non-random and predominantly associated with DNA replication dynamics in the small intestine and colon, and with transcription in the liver. These results indicate that a stable balance between various mutagenic and DNA repair processes is maintained throughout life and that the activity of these processes in adult stem cells varies between tissues.

  Study EGAS00001001682

• Targeted Linked-Read DNA-seq Analysis of Castration-Resistant Prostate Cancers

  Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, its efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. It is important to resolve the mechanisms of AR genomic rearrangements to develop new therapies and predictive biomarkers for PC. We developed a targeted linked-read DNA sequencing assay to interrogate alterations in AR and a panel of genes known to be amplified or mutated in CRPC. Linked-read DNA-sequencing libraries were generated using the 10X Genomics Chromium platform and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 using 2x150 bp settings. This targeted linked-read DNA-seq assay was used to interrogate a set of 6 benchmarking samples harboring known AR gene rearrangements and other alterations in AR, as well a panel of 6 patient-derived xenograft CRPC tumors and 23 clinical CRPC tumors. In this cohort, we identified a subset of samples that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. The data that will be made available through dbGaP are raw FASTQ files.

  Study phs003343

• Exome sequencing of patient samples from study

  Exome sequencing data from FFPE preserved patient samples and patient-derived cultures. The goal of the study is to validate patient-derived cultures. Additional goal is to understand the relationship between omics and drug response.

  Study EGAS50000000171

• Whole transcriptome seq from patient samples

  Exome sequencing data from FFPE preserved patient samples and patient-derived cultures. The goal of the study is to validate patient-derived cultures. Additional goal is to understand the relationship between omics and drug response.

  Study EGAS50000000172

• Wisconsin Longitudinal Study on Aging

  The Wisconsin Longitudinal Study (WLS) is a long-term study of a random sample of men and women, who graduated from Wisconsin high schools in 1957, and their siblings. The WLS panel started out with a panel of 10,317 members from the class of 1957. Over time a second panel of 8,734 randomly selected siblings of the original graduate panel were recruited for the study. Of these combined panel members, 9,027 survived and contributed saliva for genetic analysis. Survey data were collected from the original respondents or their parents in 1957, 1964, 1975, 1992, 2004, and 2011, and from a selected sibling in 1977, 1994, 2005, and 2011. WLS data provide a detailed record of educational, social, psychological, economic, mental and physical health characteristics of a relatively homogeneous population that is almost entirely of Northern and Western European ancestry. Saliva was first collected in 2007-2008 by mail. Additional samples were collected in the course of home interviews that began in March 2010.

  Study phs001157

• A PROSTATE TUMORGRAFT PANEL TO ACCELERATE PRECISION MEDICINE

  The management of advanced prostate cancer (PCa) has strongly evolved in the last decade with the introduction of the next generation of androgen receptor pathway inhibitors which have considerably improved patient outcomes. Most recently, the investigation of genomic landscape has provided targetable molecular alterations such as homologous gene DNA repair defects correlated with response to PARP inhibitors. Despite these significant advances, while localized PCa is generally associated with favorable outcome, metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies.

  Study EGAS00001007033

• Integration of Genomics and Transcriptomics in unselected Twins and in Major Depression

  Our goals are to develop a comprehensive understanding of the genomics of transcription in a population based unselected sample and to discover DNA and RNA biomarkers for major depressive disorder (MDD). This work is essential to developing a more complete understanding of the biological basis of MDD, a common complex trait associated with considerable morbidity, mortality, and personal/societal cost. All biological samples have been collected from well-defined populations, and are now available. First, we conduct a "genetical genomics" or eQTL study of ~800 MZ and ~800DZ twin pairs. Each subject has been assayed for genome-wide SNPs and CNVs and gene expression from peripheral blood sampled under standardized conditions. We determine the genetic architecture (genetic and non-genetic proportions of variance via twin analyses) for every transcript, and the genome-wide associations (i.e., SNP-transcript eQTL pairs). These analyses will be expanded to consider transcriptional modules. The key deliverable is a detailed catalogue of the general and specific architecture of transcription plus raw intensity files. Second, we seek to discover DNA and RNA biomarkers relevant to MDD, capitalizing on the results of a large MDD study with repeated clinical and biological assessments; we have previously shown that PB is a reasonable proxy for CNS expression and employ an advanced modelling framework: (a) Using baseline data, we identify biomarkers for MDD by comparing ~1000 controls with ~1400 MDD cases via comparisons of SNP, CNV, expression transcripts, and transcriptional modules. (b) Using longitudinal data, we contrast gene expression signatures assessed at baseline and two years later in ~200 controls and ~500 MDD cases.

  Study phs000486

• DAC-2023-07-05-Ritz (DAC-007) - Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: an observational study

  Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: an observational study This is only the location for the raw data and any check if the dataset may be relevant please refer to the MF-DAC Zenodo community (https://zenodo.org/records/11237107).

  Study EGAS50000000780

• 10x genomics single cell RNA-seq and ATAC-seq from 10 pre-menopausal patients fimbriae and ampullary part of the fallopian tube

  The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes.

  Study EGAS50000000628