Search Results - EGA European Genome-phenome Archive

Effector CD4 T Cells Convert Transient Responses to KRAS-Targeted Therapy into Long-Term Durable Remissions in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies in which reinvigoration of CD8 T cells is insufficient to induce durable long-term remissions. Direct KRAS inhibitors are clinically promising; however, acquired resistance is common. Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, with enhanced stability and high signaling potency in both humans and mice. Using an orthotopic PDAC mouse model, we evaluated responses and relapse following KRAS inhibitor treatment and demonstrated that, unlike combinations with chemotherapy or checkpoint blockade, the combination of 21h10 and KRAS inhibition is curative. Single-cell transcriptional profiling with TCR-seq revealed oligoclonal expansion of effector Th1-polarized CD4 T cells and depletion of Tregs. To evaluate the efficacy of 21h10 in human samples, we performed single-cell RNA-seq analyses on treatment-naive specimens following short-term ex vivo treatment with 21h10. This dataset consists of Illumina NovaSeq sequencing output (FASTQ files) generated from tumor libraries prepared using the 10x Genomics Single Cell 5′ Immune Profiling platform. FASTQ files are provided for gene expression (GEX), TCR, and, for multiplexed samples, HTO libraries.

Study phs004509

NCTN_NCORP: Phase III Trial of LHRH Analog Administration During Chemotherapy to Reduce Ovarian Failure Following Chemotherapy in Early Stage, Hormone-Receptor Negative Breast Cancer (S0230)

Study ID: S0230NCT Number: NCT00068601 SWOG Cancer Research NetworkSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN_NCORP: Phase III Trial of LHRH Analog Administration during Chemotherapy to Reduce Ovarian Failure following Chemotherapy in Early Stage, Hormone-Receptor Negative Breast Cancer (S0230)Trial Description: RATIONALE: Goserelin blocks hormone production in the ovaries. It is not yet known whether ovarian suppression using goserelin will prevent ovarian failure (early menopause) in women receiving chemotherapy for breast cancer.PURPOSE: This randomized phase III trial is studying how well giving goserelin together with chemotherapy works compared with chemotherapy alone in preventing early menopause in women with stage I, stage II, or stage IIIA breast cancer. Clinical data presented in the following publication(s):PMID 25738668Disease type(s): Breast Neoplasm - Breast Cancer - InvasiveClinical Dataset(s) included:NCT00068601-D1 (PMID 25738668): There is one dataset for S0230's primary publication 25738668. This dataset contains baseline characteristics, planned chemotherapy regimen, hormone receptor status, premature ovarian failure, fertility, survival, ovarian failure, and adverse event data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004261

Botensilimab, an Fc-enhanced Anti-CTLA-4 Antibody, is Effective Against Tumors Poorly Responsive to Conventional Immunotherapy

This study explores the genomic landscape associated with a novel Fc-engineered anti-CTLA-4 antibody (botensilimab) in advanced solid tumors. We seek to understand if enhancing the Fc-region affinity of anti-CTLA-4 antibodies can improve anti-tumor efficacy and expand clinical benefit to tumors poorly responsive to conventional immunotherapy. As part of an ongoing open-label, Phase 1, multicenter study, we conducted an exploratory sub-analysis of genomics data. The primary study evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of botensilimab monotherapy and in combination with an anti-PD-1 antibody (balstilimab) in participants with advanced solid tumors. RNA from formalin-fixed paraffin-embedded (FFPE) tumor biopsies and matched normal blood samples were isolated and subjected to RNA-sequencing using the Personalis ImmunoID NeXT Platform. We demonstrated that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. This genomic analysis contributes to our understanding of the molecular mechanisms underlying patient responses to Fc-engineered anti-CTLA-4 therapy and may inform future strategies to expand the clinical benefit of immune checkpoint blockade in cancer immunotherapy.

Study phs003704

Open-Label, Phase I study of NeoVax with Nivolumab in Patients with Ovarian Cancer

Personalized neoantigen-targeting cancer vaccines (PCV) in the adjuvant setting are of increasing interest across malignancies. Herein, we report the results of a first-in-disease phase I clinical trial testing the feasibility and safety of PCV for high-grade epithelial ovarian cancer (HGOC). ‘NeoVax' consisted of pools of synthetic long peptides targeting patient-specific neoantigens admixed with the immunostimulant poly-ICLC, was combined with delayed administration of anti-PD-1 antibody, and was tested in 10 patients (one newly diagnosed patient (Cohort A) and 9 patients at first recurrence (Cohort B)) with platinum-sensitive OC following standard-of-care (SOC) platinum doublet chemotherapy. Nine of 12 evaluable Cohort B patients were vaccinated (75%, 90% CI 47-93%) and 1 of 9 Cohort A patients (11%, 90% CI 0.6 – 43%). No unexpected safety signals were encountered, and no patients discontinued treatment due to toxicity. Across patients, >70% selected targets remained detectable by non-invasive cell-free DNA analysis despite a median of 6.5 months from the time of diagnostic biopsy to vaccine administration, during which patients received SOC chemotherapy. Biomarker analysis was suggestive of biologic activity of the vaccine in 6 of 10 patients and this was associated with broader tumor and vaccine-specific immune responses in blood and tumor following vaccination. Resistant tumor clones reflected diverse mechanisms affecting antigen presentation, indicative of immune-selective pressure exerted by vaccination. Overall, the interplay between the repertoire of antigens presented by the tumor and the breadth of induced immunity appeared to dictate clinical efficacy following vaccination.We are submitting:WES and WGS data from whole blood samples and tumor FFPE samplesRNA-seq data from tumor FFPE samplesscRNA-seq and scTCR-seq data from tumor biopsiesBulk TCR-seq data from CD3+ PBMC from blood samplesWGS and RNA-seq data from organoids

Study phs004380

BPH Tissues for Cell Culture and Analysis - A Patient-Derived Xenograft Model Using Benign Prostatic Tissues

Our goal was to establish and characterize a patient-derived xenograft model for benign prostatic hyperplasia (BPH) using human benign prostatic tissues. Characterization of the model was done by histology, immunohistochemistry, proteomics, and transcriptome analysis (RNAseq). The RNAseq data will be deposited in dbGaP. Subjects were undergoing prostatectomy for prostate or bladder cancer, with concurrent BPH, and consented to the use of surplus tissue for research studies. The RNAseq studies included 6 patients. Phenotypic data include patient age, sex, prostate size, serum prostate-specific antigen (PSA) level, and international prostate symptom score (IPSS). Sequencing was done on an Illumina NovaSeq 6000, and data were analyzed using Kallisto. Data are submitted as raw sequencing (fastq) files.

Study phs003692

A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab in BRCA1 and BRCA2 Mutation Carriers with Recurrent Ovarian Cancer (NCT02571725)

INST1419: A phase 1-2 study of the combination of olaparib and tremelimumab in BRCA1 and BRCA2 mutation carriers with recurrent ovarian cancer (NCT02571725) was designed to evaluate the safety and efficacy of combined treatment with the PARP inhibitor olaparib and the CTLA4 immune checkpoint inhibitor tremelimumab in women with recurrent ovarian cancer and a germline BRCA1 or BRCA2 mutation. This was a multi-site single-arm open-label study that enrolled 50 subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer between 2016 and 2020. Treatment efficacy was assessed using best overall response by modified WHO (mWHO) criteria, and secondary endpoints included disease control rate, duration of response, and progression-free and overall survival. The median age was 56 (range 39-78). All patients had measurable disease and pathogenic germline mutations in BRCA1 (72%) or BRCA2 (28%). Subjects received 300mg of olaparib by mouth, twice daily, and tremelimumab at 10mg/kg IV every four weeks for 6 doses, and then every 12 weeks for up to 24 months. Following an interim data safety monitoring review in 2018, the protocol was modified to reduce the frequency of tremelimumab infusions to 10mg/kg IV every four weeks for 4 doses, followed by infusions every 12 weeks. Exploratory biomarker assessments were performed using archived formalin-fixed paraffin-embedded (FFPE) tumor samples collected at the time of initial cytoreductive surgery from 33 subjects. Clinical characteristics and outcomes for the biomarker cohort were similar to the overall and response cohorts. Candidate biomarkers were identified based on differential gene expression in samples from patients with clinical benefit from treatment, defined as disease control for at least 12 weeks, versus those with progressive disease. For RNAseq, sample integrity was assessed using Agilent Tapestation, to ensure the DV200 was greater than or equal to 30. Sequencing was done on the Illumina NovaSeq instrument by Personalis. Gene expression used in this analysis was the normalized measure defined as transcripts per million (TPM) total RNA molecules. Welch's t-test was used to assess whether there was a difference in gene expression based on clinical benefit. The area under the receiver operating characteristic curve (AUC) was also computed for TPM gene expression based on clinical benefit. The AUC, as determined by the trapezoidal rule, was estimated by the concordance index (SAS 9.4 LOGISTIC procedure). DNA quality was confirmed if the DNA integrity number was greater than or equal to 3. Exome enrichment was performed using the Accuracy and Content Enhanced (ACE) version 4 (ACE ImmunoID NeXT) enrichment platform of Personalis. Briefly, DNA from tumor and cryopreserved PBMC samples were used to construct whole-exome capture libraries, and additional custom probes and optimized chemistry improved uniformity of coverage in sequence regions of high G-C content across the exome using ACE technology. Sequencing was performed at 20 Gigabase (G) sequencing depth for normal samples and 35G sequencing depth for tumor samples. All DNA and RNA reads were aligned to the hs37d5 reference genome built in accordance with the Personalis ACE Cancer Exome Analysis Pipeline, duplicate reads were removed, and the Genome Analysis toolkit was used to correct base quality scores and improve sequence alignment. Mutational burdens were generated using tumor-specific genomic events (SNVs, indels and fusions) of at least 5% allelic fraction that were verified using transcriptomic data. All potential neoepitopes were created for each mutation and tested for presentation, and considered putative neoepitopes if they were predicted to bind to any patient-specific alleles. The Xenium platform was used for spatial transcriptomic analyses using Xenium slides and sample prep reagents (10x Genomics). The immune panel was augmented with custom-ordered genes. Initial preprocessing included quality control, normalization, batch correction, and clustering. Cells with fewer than 20 detected features were excluded as low-quality. High-quality cell-by-gene count matrices were processed using Seurat 5.3.0, with normalization performed using SCTransform. Batch correction was carried out using Harmony integration, following standard preprocessing: individual dataset normalization, merging, PCA (RunPCA), and integration via RunHarmony. Clustering was performed on the Harmony-corrected embeddings using FindNeighbors and FindClusters (resolution = 0.03), and visualized with UMAP (RunUMAP). Cell types were initially assigned using SingleR with the HPCA reference dataset. To resolve cellular heterogeneity, subclustering was performed on select clusters using the FindSubCluster function in Seurat. Canonical marker genes used for cell type identification included CD3E for T cells, MS4A1 for B cells and EPCAM for epithelial and DCN for fibroblasts. Results from this trial demonstrated grade 3 or 4 non-hematologic toxicity in 57% of subjects. The overall response rate was 32.7% (95% CI 19.5-45.8%), with a disease control rate of 47.7% (95% CI 33.0-62.5%). In exploratory biomarker analyses, low VSTM5 or IFIT1B expression predicted treatment benefit and progression-free survival (pData available through dbGaP include RNAseq, whole exome sequencing, and Xenium spatial transcriptomic data.

Study phs004512

Epigenomics of Prostate Cancer from Cell Free Plasma

We sought to perform epigenomic characterization of prostate cancers by profiling circulating nucleosomes isolated from patient plasma using cell free chromatin immunoprecipitation followed by sequencing (cfChIP-seq). Our major findings include identification of prostate-cancer specific regulatory elements using a novel statistical method accounting for variable tumor DNA fraction in plasma, inferring transcription factor activity based on binding motif enrichment within regulatory elements, and epigenetically phenotyping patients based on clinical and genomic features. Data available in dbGaP will include cfChIP-seq and targeted sequencing from approximately 50 patients with a known diagnosis of cancer and healthy patient controls.

Study phs003482

HINTS Geo-Coded Data 2017 (HINTS 5 Cycle 1)

The Health Information National Trends Survey (HINTS) is a nationally representative survey which has been administered every few years by the National Cancer Institute since 2003. HINTS 5 includes four data collection cycles over the course of four years. The first round of data collection for HINTS 5 (Cycle 1) was conducted from January 25 through May 5, 2017 with a goal of obtaining 3,500 completed questionnaires, with a final sample including 3,285 respondents.

Study phs004210

WGS of Five Pancreatic Cancer Patients-Tumor and Normal

We performed whole genome sequence on tumor-derived and normal cell lines from patients who had terminal pancreatic cancer and consented for rapid autopsy upon their death. The 5 samples are from Dr. Christine Iacobuzio-Donahue's rapid autopsy program as reported in Boland et al. (PLOSOne, 2024, In Press, PMID 38352348).

Study phs003775

Luminal Androgen Receptor-Enriched Triple Negative Breast Cancer

This is a study to determine the efficacy of androgen receptor (AR) inhibitors in LAR (luminal androgen receptor)-enriched triple-negative breast cancer (TNBC) in the neoadjuvant setting. Twenty-four patients were treated with neoadjuvant AR inhibitor enzalutamide and paclitaxel for 12 weeks. Whole exome sequencing and RNA-sequencing was performed prior to treatment. The data for only two patients are consented for release through dbGaP. The remaining data are available under a Materials Transfer Agreement with the University of Texas MD Anderson Cancer Center.

Study phs003586

Field Effect-Informed Urine Liquid Biopsy Analysis for Assessment of Adjuvant BCG Response in Non-Muscle Invasive Bladder Cancer

The goal of this study was to develop a urine tumor DNA-based minimal residual disease liquid biopsy assay for bladder cancer that improves specificity by considering field effect mutations. We performed targeted cell free DNA sequencing on tumor, adjacent normal, and urine cell free DNA (cfDNA) from non-muscle invasive bladder cancer patients and urine cfDNA from healthy controls. We developed a method called RePhyNERX and used it to identify three molecular response classes: complete responders to surgery, responders to adjuvant Bacillus Calmette-Guérin immunotherapy, and non-responders. These molecular classifications correlated with patient outcome. We also performed RNA sequencing on tumor tissues to identify expression differences between the response classes.

Study phs004110

The Discovery and Validation of AML Prognostic Biomarkers

This study includes RNA-Seq and targeted DNA sequencing from a large collection of unsorted mononuclear cells (MNCs) and enriched viable leukemic blasts (VLBs) from bone marrow (BM) and peripheral blood (PBL) specimens collected at diagnosis from adult patients with acute myeloid leukemia (AML). Viable leukemic blasts were isolated using forward by side scatter, DAPI staining and fluorescently-labeled antibodies to CD45, CD34, CD38, and CD117. DNA and RNA were extracted using Qiagen AllPrep DNA/RNA Extraction kits. Transcriptome libraries were generated using KAPA Stranded RNA-Seq Library Preparation Kit after ribosomal RNA depletion with Roche RiboErase. Paired-end 75 bp reads were sequenced on either Illumina HiSeq 2500 (HiSeq) or NovaSeq 6000 (NovaSeq) instruments. RNA-Seq data were analyzed by the Fred Hutch Cancer Center Bioinformatics Shared Resource. STAR 2.7.1, with 2-pass mapping, was used to align reads to human reference genome GRCh37/hg19. Internal tandem duplication in FLT3 (FLT3-ITD) were identified via fragment analyses. DNA was sequenced using Illumina TruSight™ Myeloid Sequencing Panel and supplemented with in-house targeted MiSeq assays for CEBPA and NRAS exon 3 loci inadequately covered by TruSight™ platform on Illumina MiSeq instrument. Paired-end reads were first aligned to the human genome reference assembly (GRCh37/hg19) using Burrows-Wheeler Aligner (BWA, v0.7.12) and then, the resulting alignment data were processed according to the best practice of Genome Analysis Toolkit (GATK, v3.5).

Study phs002805

Southern Community Cohort Study - the Gut Microbiome Project

The Southern Community Cohort Study (SCCS) is an ongoing prospective cohort study, with the aim to investigate risk factors of cancer and other chronic diseases across 12 southeastern U.S. states: Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, and West Virginia. Approximately 86,000 adults, two-thirds Black people, between 40 and 79 years of age were enrolled from 2002 to 2009. Approximately 86% of the participants were recruited from community health centers (CHCs) and institutions providing basic health care and preventative services in underserved areas, so the cohort encompassed a substantial number of individuals characterized by low income, low education, and lack of insurance. The remaining 14% of cohort participants were recruited through mail-based general population sampling. Sociodemographic characteristics, lifestyle factors including tobacco exposure and alcohol consumption, and personal medical history were collected at cohort enrollment. Data collection methods varied by recruitment source: CHC participants completed standardized computer-assisted personal interviews, while individuals from the general population responded to self-administered mailed questionnaires. The SCCS Biospecimen Repository includes blood samples from ~40,000, mouth cells from 39,000, urines from 24,000, stool specimens from 8,000 participants, and tumor blocks from incident cancer cases. This microbiome study nested within SCCS included 594 Black participants whose stool samples were analyzed using shotgun metagenomic sequencing. We investigated associations between the gut microbiome and several physical activity measures.

Study phs004716

Childhood Cancer Data Initiative (CCDI): NCI-COG Pediatric MATCH Precision Medicine Clinical Trial

The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial provides a framework for biomarker-driven early phase trials of targeted therapies in pediatric and young adult cancer patients across the United States. Pediatric MATCH enrolled more than 1,300 patients with treatment-refractory cancers, offering access to molecular screening and investigational targeted therapies. To further advance this, matched diagnostic, refractory tumor, and normal samples from Pediatric MATCH cases were molecularly characterized, creating one of the largest comprehensive data sets available for childhood cancers. This analysis has the potential to provide novel insights into the genetics of refractory pediatric, adolescent, and young adult cancers, as well as inform potential therapeutic strategies. The following molecular characterization assays were performed: Tumor whole exome sequencing (WES) Tumor whole genome sequencing (WGS) Tumor RNA sequencing (RNA-seq) Blood whole exome sequencing (WES) Blood whole genome sequencing (WGS)

Study phs002883

Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Leukemia

The goal of this study is to molecularly characterize a large panel of pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) previously established in immune-deficient mice. These PDXs are utilized as part of the NCI-funded Pediatric Preclinical In vivo Testing (PIVOT) program to identify novel agents and combinations. Biospecimen data include next-generation sequencing (RNAseq, whole exome sequencing, DNA copy number variation), whole-genome analysis of cytogenetic abnormalities, and DNA fingerprint for quality control.

Study phs003164

APOLLO-OV: Applied Proteogenomics of High Grade Serous Ovarian Carcinoma

APOLLO is a proteogenomic study seeking to describe the major genome, transcriptome, proteome and phosphoproteome alterations, subtypes, and molecular predictors of patient outcomes. This study includes 70 high grade serous ovarian carcinoma tissues from the Gynecologic Cancer Center of Excellence (https://medschool.usuhs.edu/gso/research/gyn-cancer-center-of-excellence). Bulk and laser microdissection enriched tumor tissues were profiled by whole genome sequencing, transcriptome sequencing, MS-based proteomics and reverse phase protein arrays. Clinical and sample data include survival times, patient features, and tumor characteristics.

Study phs003488

NCTN: A Randomized Phase III Comparison of Standard-Dose (60 Gy) versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab in Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer (RTOG-0617)

Study ID: RTOG-0617 NCT Number: NCT00533949 NRG Oncology Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: A Randomized Phase III Comparison of Standard-Dose (60 Gy) versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab in Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer (RTOG-0617) Trial Description: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel, carboplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether high-dose radiation therapy is more effective than standard-dose radiation therapy when given together with combination chemotherapy with or without cetuximab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying high-dose or standard-dose radiation therapy given together with chemotherapy with or without cetuximab to see how well they work in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be removed by surgery. Clinical data presented in the following publication(s): • PMID 25601342 Disease type(s): Lung, Mediastinal and Pleural Neoplasm - Non-Small Cell Lung Cancer Clinical Dataset(s) included: • NCT00533949-D1 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D1, contains treatment arm, baseline characteristics, radiotherapy technique used, EGFR H-score, radiation treatment details, select toxicity data, and survival data. • NCT00533949-D2 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D2, contains adverse events reported in Appendix 10. • NCT00533949-D3 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D3, contains the most frequently reported adverse events reported in Tables 3 and 4. You are encouraged to view the PDF data dictionaries found in the "Documents" tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004191

Reduction of Lethal Prostate Cancer Disparities in Underserved Hispanic/Latino Populations

This pilot study investigated the genomic underpinnings of prostate cancer in Puerto Rican Hispanic/Latino men, a group disproportionately affected by this disease, in terms of incidence, mortality and aggressiveness. By examining tumors from 35 patients for specific genetic mutations and gene expression patterns using cutting-edge genomic sequencing, we aimed to identify distinct genetic profiles that could influence the course of the disease and its treatment. Our initial findings suggest the presence of unique genomic characteristics in this population, offering a promising avenue for developing personalized treatments that could reduce the health disparities observed in these men. This study underscores the importance of including diverse ethnic groups in genomic studies to ensure that the published data required for personalized cancer care are available.

Study phs004487

Blood and Marrow Clinical Trials Network - Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT CTN-0903-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To evaluate the safety and effectiveness of allogeneic hematopoietic cell transplantation for patients with hematologic malignancies or myelodysplastic syndromes and coincident-HIV infection.Background: Allogeneic hematopoietic cell transplantation (alloHCT) has been a safe and curative option for many patients with hematologic malignancies but was not well studied in the HIV+ population despite the interest in the HIV research community of the curative potential of alloHCT. Hematologic malignancies in people with HIV infection (HIV+) have been associated with poor outcomes due to opportunistic infections, but the development of antiretroviral therapy (ART) has increased the possibility of these patients achieving clinical outcomes comparable to those of the general population following stem cell transplant. The BMT CTN 0903 trial was designed to evaluate the safety and effectiveness of alloHCT for patients with HIV infection and hematologic malignancies.Participants: Patients had documented HIV infection, were a minimum of 15 years of age and had acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) in first or second complete remission (CR); Int-2 or high-risk myelodysplastic syndromes (MDS) with CCR5delta32. AlloHCT using cord blood units or T-cell depletion was not allowed. Patients with history of prior alloHCT were excluded. Patients had to meet adequate organ function. Karnofsky/Lansky performance status ≥ 70% and could not have active central nervous system disease, HIV infection resistant to all antiretroviral therapy, or opportunistic infection unresponsive to treatment.There were seventeen HIV-infected patients with acute leukemia, myelodysplasia (MDS), NHL or classical HL who were enrolled in the trial.Design: Patients with HIV infection and hematological malignancies or myelodysplastic syndromes (MDS) were treated with either reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) followed by alloHCT. RIC or MAC was at the discretion of investigator. Where feasible, an attempt was made to identify hematopoietic cell donors who were homozygotes for the CCR5delta32 polymorphism. Graft-versus-host disease (GVHD) was treated per institutional standards.Four regimens were permitted for conditioning. RIC regimens were: fludarabine and busulfan (Flu/Bu), and fludarabine and melphalan (Flu/Mel). MAC regimens were busulfan and fludarabine (Bu/Flu), or cyclophosphamide and total body irradiation (Cy/TBI). GVHD prophylaxis regimens included tacrolimus/methotrexate, tacrolimus/sirolimus, and post-transplant cyclophosphamide with tacrolimus/mycophenolate. Patients receiving busulfan-containing preparative regimens were not eligible to receive tacrolimus/sirolimus. A committee reviewed individual patient's HIV treatment history and ART options before initiation of the transplant conditioning regimen and advised changes to minimize potential drug interactions. It was recommended that ART be continued except ritonavir-containing regimens during MAC.The goal of the study was to assess the 100-day non-relapse mortality. Secondary endpoints included 100-day disease status, percentage donor chimerism, hematologic function, infections, six-month overall survival (OS), incidence of acute and chronic GVHD, immunologic reconstitution, and impact of alloHCT upon measures of HIV persistence in blood including peripheral blood mononuclear (PBMC)-associated HIV DNA and infectious virus from resting CD4+T-cells using a quantitative virus outgrowth assay.Follow-up visits occurred weekly through 8 weeks post-transplant, at 100 days, 6 months, 1 year, and 2 years.Conclusions: There was no non-relapse mortality (NRM) at 100 days, or at 6 months, and therefore no evidence to suggest that NRM is prohibitive or more than that seen in non-HIV-infected patients. The cumulative incidence of grades II-IV acute GVHD was 41%. After year one, overall survival was 59%. In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable.

Study phs004697

Niraparib in Pancreatic Cancer

Pancreatic cancer patients with pathogenic variants in DNA repair genes may benefit from PARP inhibitor therapy, but efficacy beyond germline BRCA1/2 mutations remains uncertain. This multicenter phase II trial (NCT03601923) enrolled 32 patients with advanced pancreatic cancer harboring germline or somatic pathogenic variants in BRCA1, BRCA2, PALB2, ATM, or CHEK2 who had not progressed on prior platinum-based chemotherapy. Patients received niraparib 200-300 mg daily. Here we deposit the whole exome samples of six patients from the study (N=13 total samples). Patients P02, P03, P06, and P21 have matched tumor-normal blood pairs; patient P22 has a single tumor sample; and patient P30 has four tumor samples collected at different timepoints for longitudinal analysis.

Study phs004405

The Cancer Dependency Map (DepMap)

The Cancer Dependency Map (DepMap) aims to accelerate precision cancer medicine by creating a comprehensive map of tumor vulnerabilities. The DepMap project genomically profiles a wide range of cancer models and characterizes them for their sensitivity to genetic and compound perturbations. The data is computationally analyzed to create a systematic overview of the genetic dependencies and compound sensitivities of cancer types and the predictive biomarkers that point to patient populations most likely to benefit from targeting of these vulnerabilities. The DepMap public portal has become a comprehensive resource to identify cancer vulnerabilities by providing datasets at scale, cutting-edge computational tools, and sophisticated visualization tools that together have accelerated the discovery of novel targets and biomarkers. Please visit Depmap.org to access the public portal.

Study phs003444

KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

Study phs002801

Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis

We recruited cases of Langerhans cell histiocytosis (LCH) who were recruited to the Children's Oncology Group Childhood Cancer Research Network, Project:EveryChild projects, or to a local patient biobank to conduct an expanded genome-wide association study for risk variants and to perform post-GWAS analysis of a previous hit in the SMAD6 gene. Publicly available control data were used for our analyses; however, here we provide the SNP array data and targeted SMAD6 sequence data for the LCH cases and some non-LCH cases included in the analysis.

Study phs004547

MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

Study phs003688

Metabolic Biomarkers in Thoracic Cancers

Here we present RNA sequencing (RNA-Seq) of non-small cell lung cancer (NSCLC) and adjacent lung tissue. These samples were acquired from primarily untreated, surgically resected primary tumors. The first analysis published with this data was to determine the metabolic signatures between primary tumors and adjacent lung tissue.The associated clinical trial (NCT02095808) includes patients with many kinds of thoracic cancers, including NSCLC and other diseases, such as thymoma and esophageal adenocarcinoma. However, the current dbGaP data is focused on the NSCLCs described in the associated paper.

Study phs003880

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