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• Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

  3784 whole genome sequencing bam files were generated from plasma cell-free DNA of healthy individuals and patients with cancer. Paired reads were mapped to hg19 human reference genome.

  Study EGAS00001006553

• Gencode_741K

  The individuals were genotyped for the Illumina Human Omni Express Bead Chip (OmniExpress), containing 741,000 SNPs. 22 samples were excluded with more than 10% missing genotypes

  Dataset EGAD00010001640

• Whole-exome sequencing profiling of patients with metastatic prostate cancer at VHIO

  Metastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations, which have prognostic and predictive value. Routine clinical implementation of next-generation sequencing (NGS) is still limited. We investigated the association between genomic and functional loss of HRR, using NGS and a RAD51 immunofluorescence (RAD51-IF) iprimary or metastatic biopsies from patients with stage IV prostate cancer. Whole-exome sequencing was pursued for paired tumor-normal samples.

  Study EGAS50000000736

• RNAseq of medulloblastoma data (MB_COMICS cohort)

  Medulloblastoma (MB) is the most common malignant brain tumor in children. It is a neuroectodermal tumor located in the cerebellum. International consensus recognizes four distinct subgroups of MBs including Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4) with distinct molecular characteristics, prognoses, and mortality rates in patients. Here, we have compiled and evaluated a large international MB cohort for which we generated transcriptomic data (RNAseq) for 208 primary MB patient samples.

  Study EGAS50000000410

• Exome_sequencing_of_a_cohort_of_Rett_syndromelike_patients

  The aim of the project is the definition of the molecular defect in a cohort of Rett-like patients negative for mutations in known disease genes. To this aim, a number of unrelated trios (patients plus parents) will be analysed by exome sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002059

• GENEVA Genes and Environment Initiatives in Type 2 Diabetes (Nurses' Health Study/Health Professionals Follow-up Study)

  Type 2 diabetes mellitus (T2D) affects approximately 21 million individuals in the U.S., or almost 10% of the U.S. adult population. Because diabetes is determined by both genetic and environmental factors, a better understanding of the etiology of diabetes requires a careful investigation of gene-environment interactions. The Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS) are well-characterized cohort studies of women and men for whom stored blood and DNA samples are available as well as detailed information on dietary and lifestyle variables. The major goals of the project include: 1. To conduct a GWA analysis among 3,000 cases of T2D and 3,000 healthy controls in NHS/HPFS cohorts. 2. To use information on the joint effects of genes and a list of carefully selected environmental exposures at the initial screening stage to test gene-environment interactions. This approach optimizes our power to detect variants that have a sizeable marginal effect and those with a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. For this analysis, we have developed a joint test of genetic marginal effect and gene-environment interaction. This flexible two-degree-of-freedom test generally provides greater power than standard methods and has the potential to uncover both marginal genetic effects and stratum-specific effects. The Version 1 (v1) dbGaP release of data from the GENEVA Diabetes Study (NHS/HPFS) includes data from the NHS only. The Version 2 (v2) dbGaP release includes data from both the NHS and HPFS. 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 type 2 diabetes mellitus through large-scale genome-wide association studies of well-characterized cohorts of nurses and health professionals. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000091

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003138

• Characterization of the Gut-Associated Microbiome in Inflammatory Pouch Complications Following Ileal Pouch-Anal Anastomosis

  This study involved evaluation of the tissue associated microbiome of the ileal pouch following surgery for ulcerative colitis (UC) or familial adenomatous polyposis (FAP). Individuals were recruited, with biopsies taken from the ileal pouch and the pre-pouch ileum, microbial DNA was extracted and sequenced using 454 pyrosequencing. Total bacterial community structure and abundance were evaluated to determine which changes were characteristic of inflammatory phenotypes including pouchitis (inflammation of the ileal pouch) and a Crohn's disease-like phenotype.

  Study phs000659

• COVID_Methyl_scRNA

  DAC for the study of whole-genome enzymatic DNA methylation sequencing and single-cell RNA sequencing of nasal cells from COVID-19 patients. Nasal swabs were collected from COVID-19 patients during the acute phase of infection as well as 3 and 12-months post-infection. Cells isolated from nasal swabs were subjected to whole-genome enzymatic DNA methylation sequencing (n=33) and scRNA-seq (n=24). For n=12 former COVID-19 pateints, follow-up samples were collected at 3 and 12 months post-infection and subjected to scRNA-seq.

  Dac EGAC50000000197

• Resolving_the_Genetic_Architecture_of_Aseptic_Loosening_After_Total_Hip_Replacement

  This is a genome-wide association scan of aseptic loosening after total hip replacement in a Norwegian population. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001883

• Genomic analysis reveals novel secondary drivers and progression pathways in skin basal cell carcinoma

  Basal cell carcinoma of the skin (BCC) is the most common malignant neoplasm in humans. BCC is primarily driven by the aberrant activation of the Sonic Hedgehog (Hh) pathway. However, its extensive phenotypical variation remains to be explained. The genetic profiling of 293 BCCs revealed the highest mutation rate observed in cancer (65 Mutations/Mb), with strong prevalence of UV-light signature mutations. 85% of BCCs harbored mutations in Hh pathway genes: mutually exclusive PTCH1 (73%) and SMO (20%) (P=6.6x10-8), SUFU (8%), and in TP53 (61%). 85% of BCCs also harbored secondary driver mutations in other genes implicated in BCC tumorigenesis. Recurrent secondary driver mutations were observed in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), RAC1 (1%) and N/K/H-RAS (2%). Loss of function (LoF) and deleterious missense mutations were observed in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). In line with the mutational profiles detected by RNAseq, we observed activation of the Hh pathway as well as upregulation of target genes of the Hippo-YAP pathway and activation of MYCN target genes. The functional analysis of the novel tumorigenic driver mutations in MYCN, PTPN14 and LATS1 demonstrates their relevance in BCC tumorigenesis and provides an expanded molecular understanding of BCC.

  Study EGAS00001001540

• 10X single-cell Multiome (RNA+ATAC) and single-cell RNAseq of xenograft-derived HSPC, progenitors and myeloid progeny

  10X genomics chromium single-cell ATAC+RNA (Multiome) was use to prepare single-nucleus RNA- and ATAC-seq libraries for human HSPC sorted from xenografts recovered from inflammatory challenge. 10X genomics 3' kits were used to prepare single-cell RNA-seq libraries for committed progenitors and myeloid cells from the same xenografts. These were sequenced on an Illumina NovaSea 6000 platform; BAM files are provided. Samples from 3 conditions were sequenced for each cell type; 3 chromatin accessibility runs and 9 gene expression runs are provided.

  Dataset EGAD50000002328

• The Melbourne Urological Research Alliance (MURAL) Collection of Patient-Derived Models of Prostate Cancer

  1. Low-Dose Carboplatin Modifies the Tumor Microenvironment to Augment CAR T Cell Efficacy in Human Prostate Cancer Models.Single-cell RNA sequencing (scRNA-seq) was performed to analyze the transcriptional modifications in the tumor microenvironment of prostate cancer patient-derived xenografts (PDX). The analyzed PDX tumor was PDX-287R from the MURAL collection of PDXs (PMID: 34413304). Mice harboring PDX tumors were treated with the carboplatin chemotherapy, and tumors were harvested 3 weeks later. RNA sequencing (RNA-Seq) was used to define immune and non-immune cell populations and anti-tumor innate immune signaling within the tumor microenvironment.To investigate the response of tumor cells to carboplatin treatment in more detail, RNA-Seq was performed on FACs-isolated tumor cells from PDX-287R at one week post-treatment. Gene set enrichment analysis showed an enrichment for apoptotic pathways, with significantly increased expression of the pro-apoptotic genes FAS, BAX, BBC3, IFI6, and JUN. Previously, carboplatin has been shown to activate the cGAS/STING pathway, and here we also found an increase in STING signaling, with an enrichment for the cytosolic DNA sensing pathway and increased expression of STING1, STAT1 and STAT2. There was also a significant increase in the expression of genes involved in T cell chemotaxis, including CXCL10, CXCL11, and CCL20. Collectively, carboplatin-induced cell death in tumor cells likely initiated a pro-inflammatory phenotype in prostate cancer PDXs.2. Co-Targeting BET, CREBBP, and EP300 Inhibits Neuroendocrine Signaling in Androgen Receptor-Null Prostate Cancer.The landscape of castration-resistant prostate cancer (CRPC) is characterized by a multitude of phenotypes, among which neuroendocrine disease holds a prominent position, each displaying unique responses to therapeutic interventions. The efficacy of inhibitors targeting BET and CREBBP/EP300 in prostate cancer treatment is widely acknowledged, primarily due to their ability to attenuate androgen receptor (AR) signaling. However, the effectiveness of these inhibitors in prostate cancers devoid of AR remains uncertain.This investigation sought to elucidate the role of BRD4, CREBBP, and EP300, which are co-expressed in both AR-positive and AR-null prostate cancer. Our study revealed that a compound targeting all three proteins, NEO2734, exhibited efficacy in suppressing the growth of organoids from both AR-positive and AR-null tumors, as evidenced by alterations in viability, size, and cellular composition. Furthermore, NEO2734 treatment consistently led to transcriptional downregulation of cell cycle pathways across various models. In the context of neuroendocrine prostate cancer (NEPC), NEO2734 demonstrated notable efficacy. Treatment with NEO2734 resulted in decreased expression of ASCL1 and other neuroendocrine markers (including SYP) , accompanied by a reduction in tumor growth in vivo. These findings collectively underscore the potential of epigenome-targeted inhibitors in impeding the growth of neuroendocrine prostate cancer, by disrupting lineage regulators in a phenotype-dependent manner. Consistent with the NEPC organoids and explants, NKX3-1 was upregulated in NEO2734-treated PDXs.In this study, we examined the impact of NEO2734 treatment on 6 organoids (treated for 24 hrs), 3 explants treated with JQ1 (for 48 hrs) and 2 PDXs (at two time points) using bulk RNA sequencing (RNA-Seq). These results are available through this dbGaP submission. The implications of these results warrant further exploration and development of compounds possessing similar activities for clinical applications. The ability of NEO2734 to mitigate the growth of both AR-positive and AR-null prostate cancer underscores its potential as a versatile therapeutic agent. Moreover, its efficacy in targeting neuroendocrine phenotypes offers promising avenues for addressing a subtype of CRPC that poses significant clinical challenges. In conclusion, this study sheds light on the intricate interplay between epigenetic regulators and prostate cancer phenotypes. The observed effects of NEO2734 on growth inhibition and phenotype-specific disruption highlight the importance of continued research into compounds with similar epigenome-targeting mechanisms for advancing precision medicine approaches in the treatment of prostate cancer.3. Defining Focal Neuroendocrine Differentiation as a Transcriptionally Distinct Form of Prostate Cancer Pathology Characterized by the Expression of Androgen ReceptorsThe study aimed to understand the transcriptional differences among different neuroendocrine pathologies of prostate cancer. The study hypothesized that the diverse neuroendocrine pathology observed in prostate might be attributable to differences in transcriptional level that remain hidden in bulk RNA-Seq data. To investigate, we employed scRNA-seq to generate gene expression profiles of 18,632 individual tumor cells from 9 PDX models representing five distinct neuroendocrine pathologies of prostate cancer. Our analysis identified 3-8 transcriptionally distinct sub-populations per PDX. The expression of key oncogenic signaling pathways and master regulator activity varied across in neuroendocrine pathologies, with each type of pathology displaying a unique set of transcriptional sub-populations. We discovered that, like the amphicrine pathology, focal neuroendocrine differentiation (focal NED) cells maintain androgen receptor (AR) signaling. However, the expression profiles of focal NED cells differed from the other pathologies, indicating it should be considered as a distinct type of neuroendocrine pathology in prostate cancer. Analysis of copy number alterations suggested little clonal divergence between focal NED cells and neighboring adenocarcinoma cells, emphasizing the transcriptional distinctiveness of focal NED.Overall, the findings suggest potential differences in treatment approaches for tumors from prostate cancer patients showing neuroendocrine pathology, especially focal NED.4. Reprogramming of Androgen Receptor Activity in Castration-Resistant Prostate Cancer is Shaped by Truncated Variants.Under the influence of treatments that target the androgen receptor (AR) axis, prostate cancer cells undergo various changes to the AR gene. This includes the production of truncated AR variants that lack the ligand binding domain and are constitutively active. However, the exact role of these truncated variants in shaping the AR signaling axis and their importance in therapy resistance is not yet fully understood. By examining the AR cistrome in a group of patient-derived prostate cancer models with different mechanisms of castration resistance, we observed diverse changes in AR activity in metastatic prostate cancer, including castration-resistant models. Specifically, we identified a unique subset of tumors characterized by the expression of ARv567es, a variant resulting from structural rearrangements of the AR gene. Tumors positive for ARv567es showed a distinct AR binding profile and epigenome compared to those without ARv567es, which was linked to an altered transcriptional profile. The presence of ARv567es is associated with poor responses to treatments, such as castration and bipolar androgen therapy (BAT), regardless of the presence of full-length AR. This involves disruption of the autoregulatory loop that controls AR gene transcription and reduced transcriptional responses to treatment. Overall, this study demonstrates that ARv567es can lead to transcriptional reprogramming in advanced prostate cancer and drive therapy resistance. 5. The MURAL Collection of Prostate Cancer Patient-Derived Xenografts Enables Discovery Through Preclinical Models of Uro-Oncology.We created a comprehensive PDX resource for prostate cancer to facilitate the rapid and systematic evaluation of new therapies. This collection includes 59 tumors from 30 patients, gathered between 2012 and 2020, aligning with the availability of abiraterone and enzalutamide in the clinic. The PDXs cover the clinical, pathological, and genomic spectrum of prostate cancer, ranging from treatment-naïve primary tumors to castration-resistant metastases. We characterized heterogeneity in adenocarcinoma and neuroendocrine phenotypes using bulk and single-cell RNA sequencing. Additionally, organoids were cultured from PDXs, enhancing our preclinical study capabilities. Employing a 1x1x1 design, we quickly identified tumors with responses to combination therapies. To manage the distribution of PDXs, we established the Melbourne Urological Research Alliance (MURAL). This PDX collection significantly enhances our ability to test and prioritize effective treatments for future clinical trials in prostate cancer.6. Prostate Cancer Associated Fibroblasts Have Distinct Morpho-Mechanical Features That Are Associated With Patient Outcome.The tumor stroma, including cancer-associated fibroblasts (CAFs), has a crucial role in tumor progression. This study focused on the morphological and mechanical properties of CAFs and normal prostatic fibroblasts. The findings revealed that CAFs had distinct morphological and mechanical characteristics compared to normal fibroblasts, such as differences in nuclear size, shape, F-actin arrangement, cellular volumes, and elasticity. Additionally, the study correlated these biophysical properties with transcriptomic data, identifying pathways and cellular components linked to the observed changes. Overall, high-throughput assessments of biophysical properties in prostate cancer cells and stromal components may serve as predictive tools for patient outcomes and help identify new therapeutic approaches targeting the tumor stroma.

  Study phs003369

• Study of Leukemia Stem Cells in B-ALL

  This study focused on the biologic properties of human B acute lymphoblastic leukemia (ALL) stem cells. We used human leukemia cell lines, primary patient specimens, and patient derived xenografts in experiments using ChIP-seq, bulk RNA sequencing, single cell RNA sequencing, and CITE-seq.

  Study phs002492

• Whole-exome sequencing of intrahepatic cholangiocarcinoma tumors with matched normal tissue from the Medical Center – University of Freiburg

  This dataset contains raw whole-exome sequencing data from 40 samples of intrahepatic cholangiocarcinoma patients, including tumor and matched normal tissue. Samples were sequenced on the NovaSeq platform. The cohort is part of a proteogenomic profiling study integrating genomic and proteomic data.

  Dataset EGAD50000001926

• whole exome sequencing (WES) data of the HIPO head and neck cancer (HNC, n=83)

  Paired whole exome sequencing data of the HIPO head and neck cancer (HNC) (n=83), using Agilent SureSelect V4+UTRs and V6+UTRs with the sequencing platforms HiSeq2000 and HiSeq2500. The reads were aligned to hg19. This is part of project H019.

  Dataset EGAD00001006336

• Single-cell RNA-sequencing of CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) from a Phase I clinical study in paediatric ALL: CARPALL

  Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.

  Dataset EGAD00001010018

• Foetal_phylogeny_8pcw___WGS_of_LCM_tissues

  This study relates to the overall project of constructing the phylogeny of foetal haematopoiesis. This is an additional project relating to pre-existing work in projects 2043, 2169, 2243 and 2244. This project is to perform WGS (to around 40X) of polyclonal LCM tissues from the 8pcw foetus that have previously undergone library prep and targeted sequencing only. This work is to address reviewers comments for the publication of this work.

  Study EGAS00001004674

• HELIUS cohort gut microbiome batch2

  The gut microbiota composition is unique to every individual but is shaped by common factors including diet, lifestyle, medication use, early-life determinants, living environment or genetics. Most of these factors may be influenced by ethnicity. This study explored variations in fecal microbiota composition in 6048 individuals with different ethnic backgrounds living in the same geographical area (Amsterdam, the Netherlands). The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Dataset EGAD00001009732

• HELIUS cohort gut microbiome

  The gut microbiota composition is unique to every individual but is shaped by common factors including diet, lifestyle, medication use, early-life determinants, living environment or genetics. Most of these factors may be influenced by ethnicity. This study explored variations in fecal microbiota composition in 6048 individuals with different ethnic backgrounds living in the same geographical area (Amsterdam, the Netherlands). The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Dataset EGAD00001004106

• BestAgeingMiRNA

  Processed miRNA expression profiles and clinical phenotype data from patients with cardiovascular diseases (dilated cardiomyopathy, acute coronary syndrome, ischemic cardiomyopathy, and coronary artery disease) and healthy controls. MicroRNA expression was assessed using Agilent human miRNA microarrays with RMA normalization and log2 transformation. Dataset includes expression values for all detected case/control miRNAs from miRBase v21, along with clinical metadata including disease status, age, sex, and study center.

  Dataset EGAD00010002788

• Mutant clone mapping in normal oesophagus (2019-04-03)

  We will use targeted exome sequencing to examine normal appearing epithelium and whole exome and whole genome sequencing of microdissected clones identified by immunostaining Some of the samples will be of low DNA concentration and therefore may require extra rounds of amplification during library prep. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004888

• Sequencing data for ICGC Oesophageal Adenocarcinoma tissue samples - 100_all_samples

  All samples from the "100" project

  Dataset EGAD00001001457

• Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN Study)

  This research study focuses on the genomic and psychological environmental effects on blood pressure among mothers and their children. The study includes 250 mothers who self-identify as AA/black, and 250 children between the ages of 3 and 5 years old at the time of enrollment. The study is longitudinal and data collection interviews are scheduled every six months for two years after enrollment, for a total of four participant interviews. Assessment is as follows: genetic (time 1 only) and psychological factors (every six months for two years).

  Study phs001792

• Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

  Study phs000605