Search Results - EGA European Genome-phenome Archive

Aberrant Activation of Wound Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells

Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression.Using single-cell transcriptomics (scRNA-seq), we characterized genome– and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models.Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.

Study phs003569

Precision Interception of Gastric Cancer Precursors Through Molecular and Cellular Risk Stratification

The GAstric Precancerous conditions Study (GAPS, NCT04191551) is a cross-sectional study of patients undergoing endoscopy who are at increased risk of gastric cancer. Enrolled patients are administered a standardized questionnaire, undergo clinical biopsy collection using the Sydney system, and consent for the collection of saliva, blood, and additional gastric tissue. All patients are scored for intestinal metaplasia using the operative link on gastric intestinal metaplasia (OLGIM) scoring system.

Study phs003648

NCTN: A Randomized Phase III Trial of Three Different Regimens of CPT-11 Plus 5-Fluorouracil and Leucovorin Compared to 5-Fluorouracil and Leucovorin in Patients with Advanced Adenocarcinoma of the Colon and Rectum (N9741)

Study ID: N9741 NCT Number: NCT00003594 Alliance for Clinical Trials in Oncology Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: A Randomized Phase III Trial of Three Different Regimens of CPT-11 plus 5-Fluorouracil and Leucovorin compared to 5-Fluorouracil and Leucovorin in Patients with Advanced Adenocarcinoma of the Colon and Rectum (N9741) Trial Description: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy is most effective in treating advanced colorectal cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients who have advanced, recurrent, or metastatic colorectal cancer that cannot be treated with surgery or radiation therapy. Clinical data presented in the following publication(s): PMID 14665611 Disease type(s): Gastrointestinal Neoplasm - Colorectal Cancer Clinical dataset(s) included: NCT00003594-D1 (PMID 14665611): The NCT00003594-D1 dataset is one of 4 datasets associated with PubMed ID 14665611. This dataset contains information regarding patient-level information including eligibility, treatment arm, baseline characteristics, grade 4 and 5 toxicity data, and best response. It also includes information to analyze overall survival and time to progression. NCT00003594-D2 (PMID 14665611): The NCT00003594-D2 dataset is one of 4 datasets associated with PubMed ID 14665611. This dataset contains information per patient, per cycle regarding dosing, reasons for treatment delays, and overall response assessment status. NCT00003594-D3 (PMID 14665611): The NCT00003594-D3 dataset is one of 4 datasets associated with PubMed ID 14665611. This dataset contains information per patient, per cycle, per adverse event during treatment. NCT00003594-D4 (PMID 14665611): The NCT00003594-D4 dataset is one of 4 datasets associated with PubMed ID 14665611. This dataset contains information per patient regarding end of treatment timing and reason. Additional genomic data are available for this trial under phs001290. 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 phs004259

A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

This study investigated the genomic landscape of tumors from patients with inherited mutations in DNA repair genes. The aim of this study was to determine the relationship between locus-specific loss of heterozygosity (LOH) and genomic signatures of homologous recombination-based DNA repair (HR) deficiency in tumors associated with pathogenic germline variants in DNA repair genes. Cohorts of pathogenic germline variant (PGV) carriers with different cancer types were identified via a cancer genetics registry and clinical practice at Penn Medicine and through our collaborator network. Tumors were analyzed with next generation sequencing (whole exome and/or targeted panel sequencing) with or without transcriptomic analyses. Sub-study #1 "Non-breast/ovarian tumors in germline BRCA1/2 carriers". This study investigated primary non-breast/ovarian tumors that arise in individuals with BRCA1/BRCA2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Individual WES data from DNA samples from tumor and normal are available. Sub-study #2: "Breast tumors in germline CHEK2 carriers". This study investigated primary breast tumors that arise in individuals with CHEK2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors. Individual WES data from DNA samples from tumor and normal and RNAseq data from tumor are available. Sub-study #3: "Breast tumors in germline TP53 carriers". This study investigated primary breast tumors that arise in individuals with TP53 pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal breast tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available. Sub-study #4: "Prostate tumors in germline DNA repair carriers". This study investigated prostate tumors that arise in individuals with a variety of pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal prostate tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available.

Study phs003348

Cellular and Molecular Profiling of Epithelial Ovarian Cancers and Associated Normal Tissues

This collection of data includes bulk RNA-seq and whole genome bisulfite sequencing (WGBS) for ovarian cancer samples (microdissected into carcinoma and stroma compartments), as well as single-cell RNA-seq (scRNA-Seq) and bulk WGBS and enzymatic methyl-seq (EM-seq) normal human Fallopian tube samples. The data from the ovarian cancer samples was collected to understand cellular and molecular alterations associated with histological and molecular subtypes of ovarian cancer. Data for these samples are included in Djirackor, Heinze et al. (accepted at Cancer Research). The scRNA-Seq data was generated to identify the developmental trajectory, cell type composition, and point towards the cell-of-origin for high grade serous ovarian carcinoma (HGSOC). Further, this was intended to establish a normal RNA reference for the cancer data. Results from this study are described in Johnson, Majewski et al. (accepted at Nature Communications, preprint PMID: 40475517). The data from bulk DNA methylation on normal Fallopian tubes was used to optimize the bisulfite-conversion process for the cancer samples and to serve as an epigenetic reference in the cancer studies. This data is described in Morrison et al. (PMID: 34147133). Any questions can be directed to Hui Shen (hui.shen@vai.org).

Study phs004702

FIGHT-207: Anonymized Genomic Alterations and Clinical Responses

Background: FIGHT-207 was a phase 2 study of the FGFR1-FGFR3 inhibitor pemigatinib in patients with previously treated, locally advanced/metastatic or unresectable solid tumor malignancies harboring activating fibroblast growth factor receptor (FGFR) gene alterations. Population information: 107 patients were divided into 3 cohorts: FGFR1–FGFR3 fusions/rearrangements; n=49 Activating FGFR1–FGFR3 non-kinase domain single nucleotide variants (SNVs); n=32 FGFR1–FGFR3 kinase domain mutations or variants of unknown significance (VUS) with potential pathogenicity; n=26 Participants on study had tumors that were grouped into the following histologies based on ≥ 5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial, uterine), central nervous system (glioblastoma, low-grade pediatric glioma, astrocytoma), pancreatic cancer, breast cancer, urothelial tract/bladder cancer, non-small cell lung cancer, and other (adrenal cancer, anal cancer, cancer of unknown primary origin, colorectal cancer, gastric/gastroesophageal cancer, gallbladder cancer, giant cell bone tumor, head and neck cancer, lung neuroendocrine cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, renal cell cancer, sarcoma, solitary fibrous tumor). Among the efficacy-evaluable participants, 99 had both independent review committee (IRC) central best overall response (BOR) and tissue NGS- data; 2 additional patients had Not Evaluable (NE) as central BOR Baseline tissue targeted NGS data (F1CDx, Foundation Medicine Inc.) of genomic alterations are reported for N=101 participants Baseline plasma targeted NGS analysis (PredicineCare, Predicine Inc.) of genomic data are reported for N=83 participants; data at disease-progression are reported for N=78 participants. Principal Findings: The FIGHT-207 study provided evidence of clinical benefit of pemigatinib in multiple histologies, explored the clinical actionability of various FGFR1-FGFR3 gene alterations, and leveraged the depth of translational data from targeted NGS analysis of baseline samples and plasma samples obtained at baseline and end of treatment to provide key insights into the biology of FGFR inhibition and the clinical utility of FGFR inhibitors. The FIGHT-207 article (pending in Nat.Med. NMED-A128973B) reports evidence suggesting clinical acquired resistance to FGFR inhibition via secondary FGFR mutations as well as emerging co-mutations in other oncogenic and tumor suppressor pathways. This study also provides evidence of acquired resistance to FGFR inhibition in multiple histologies beyond cholangiocarcinoma and urothelial cancers in a systemic correlative analysis of post-progression ctDNA in a trial. Data available through dbGaP: Anonymized information for 101 participants with both IRC central BOR evaluation (including 2 patients with NE as BOR) and tissue NGS data, including tumor histology, enrollable FGFR alteration, and outcome. Genomic alterations determined by baseline tissue NGS (F1CDx, Foundation Medicine Inc.) Genomic alterations determined by plasma NGS analysis (PredicineCare, Predicine Inc.) of ctDNA analysis at baseline (n=83) and at end of treatment/ disease progression (n=78) including genomic alterations that were not assessed to be Germline SNPs.

Study phs003590

Pursuing Molecular Biomarkers to Guide Adjuvant Therapy for HPV+ Head and Neck Cancers After Transoral Robotic Surgery

Human papillomavirus-positive oropharyngeal squamous cell carcinomas (HPV+ OPSCCs) represent a distinct subset of head and neck cancers that are rapidly increasing in incidence. Despite the generally favorable prognosis of HPV+ OPSCCs, compared to HPV-negative counterparts, due to higher treatment responsiveness and improved survival, a subset of patients experiences disease recurrence, leading to poor clinical outcomes. The identification of high-risk patients through molecular stratification could enable personalized therapeutic strategies, including intensified treatment or novel interventions. This study focuses on the molecular profiling of treatment-naïve primary HPV+ OPSCCs, aiming to identify molecular characteristics associated with tumor recurrence. In this study, we compared molecular profiles of primary tumors that recurred with those of non-recurrent control tumors to uncover key molecular features linked to recurrence.

Study phs003889

HINTS Geo-Coded Data 2013 (HINTS 4 Cycle 3)

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 4 includes four mail-mode data collection cycles over the course of three years. The third of these cycles (Cycle 3) was conducted from September 2013 through December 2013, including a total of 3,185 respondents.

Study phs004208

Basal-to-Inflammatory Transition Contributes to Basal Cell Carcinoma Therapy Resistance via Crosstalk with a Pro-Inflammatory Stromal Niche

Overcoming tumor evolution and inducible resistance states remain the main challenge to creating successful anti-tumor therapies. The body's cancer-associated inflammatory response is a double-edged sword having ill-defined pro- and anti-tumor properties. Our group previously identified a basal cell carcinoma (BCC) tumor-intrinsic resistance pathway called basal to squamous cell carcinoma transition (BST). However, tumor resistance driven through the complex dynamics of tumor interactions with the inflammatory response remains poorly studied. Here, employing a multipronged approach combining human tumor single-cell transcriptomics, single-cell chromatin accessibility (scATAC-Seq) study, CODEX multiplexed imaging, spatial transcriptomic along with functional validation, we have identified a surprising inflammation-associated SMOi therapy enriched tumor epithelial cell state we term basal-to-inflammatory transition (BIT). Marked by CHI3L1, TAGLN, ITGAV, and VCAM1, BIT arises in spatially distinct neighborhoods from BST in a subset of naive BCCs. While BST tumor epithelium occurs within the central cores of tumor nodules, BIT tumor epithelium arises in a specialized inflammatory environment defined by a tumor associated TREM1 myeloid signature. IL1 and OSM secreted by TREM1 myeloid cells activate the inflammatory NF-kB family of transcription factors within the BIT tumor epithelium. Strikingly, IL1 and OSM ligands are sufficient not only in inducing the BIT tumor state in vitro and in vivo in a synergistic fashion but also in lowering the sensitivity of human BCC explant tumors to SMOi treatment. This work provides critical insights into the BIT-resistant state as a novel targetable tumor state driven by a specialized inflammatory microenvironment.

Study phs003437

Blood and Marrow Clinical Trials Network Evaluating Corticosteroids with Mycophenolate Mofetil vs. Corticosteroids with Placebo as Initial Systemic Treatment of Acute GVHD (BMT-CTN-0802-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.ObjectivesExplore the difference in response and survival rates for individuals with acute graft versus host disease (aGVHD) who received mycophenolate mofetil (MMF) plus corticosteroids versus corticosteroids alone.BackgroundIndividuals with certain cancers, genetic blood diseases, autoimmune diseases, and skeletal dysplasia may be candidates to receive an allogeneic hematopoietic stem cell transplantation (HSCT) as a potentially curative measure. A common and often fatal complication of receiving the transplant is acute graft-versus host disease (aGVHD). Historically, aGVHD has been treated with corticosteroids alone but favorable response rates are less than half prompting the need for better treatment options.ParticipantsAdult and pediatric participants were eligible for this study if they were the recipient of an allogeneic HSCT and newly diagnosed with aGVHD. Participants also needed to be able to swallow the MMF or placebo capsules and have an absolute neutrophil count > 500 cells per μL without growth factors. Disqualifiers for study eligibility included receipt of MMF or mycophenolic acid within 7 days of screening, uncontrolled infections, hepatic veno-occlusive disease, chronic GVHD, or renal failure on dialysis.A total of 235 patients participated in the study. Participants were randomized into either a treatment or placebo group. There were 116 participants in the treatment or MMF arm and 119 participants in the placebo arm.DesignBMT CTN 0802 was a phase 3 multicenter randomized double-blinded trial. Randomization was stratified by transplant center and grade of aGVHD (I-II vs III-IV) at study entry. Eligible participants who required GVHD therapy were treated within 72 hours of enrollment. All patients in the study received corticosteroids at a dose of prednisone 2 mg/kg per day orally (or methylprednisolone 1.6 mg/kg per day IV). Patients were also given MMF or the placebo at a dose of 1000 mg or 20 mg/kg (for patients Response to treatment was classified as complete, partial, progression, no response, or flare. Complete response (CR) was defined as complete resolution of all signs and symptoms of aGVHD, and a partial response (PR) was defined as improvement of 1 stage in 1 or more organs involved by GVHD without progression in others. Progression was defined as worsening in 1 or more organs, and no response was defined as stable disease or absence of improvement in any organ involved by GVHD within 14 days of therapy initiation. A flare in GVHD was defined as any increase in symptoms or therapy for aGVHD after an initial response (CR or PR). All toxicities were reported regardless of whether they were thought to be related to the study treatment.Adult study participants who were able to communicate in English also completed the MD Anderson Symptom Inventory (MDASI), a tool used to measure quality of life. Participants completed the inventory at enrolment and at day 56 ± 7 days.The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy.ConclusionsResults for this study concluded that the addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. There was also no difference between the treatment arms in regards to quality of life measures (Bolanos-Meade J, Logan B, Alousi A et al., Blood. 2014;124(22):3221-3227).

Study phs004840

Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

Study phs003251

Sequencing Data from Patient-Derived Models of Pediatric Cancer

Pediatric cancer can take decades of life from patients and devastate families. To design improved treatments we must understand the pathogenesis and molecular mechanisms underlying development of these diseases. Tumor samples from patients are precious resources that give unique biological insights. To extend the utility of these samples, we utilize patient derived xenograft (PDX) models. These models are created by growing patient tumor samples in immune compromised mice. This increases the volume of samples available for study and enables in vivo testing. We generated single cell RNAseq data from pediatric PDX models to characterize the tumor, explore microenvironmental interactions and test treatments. This study aims to provide a warehouse for data generated from PDX models. Additional data will be added as it becomes available and is published.

Study phs004719

Genomic Characterization CS-MATCH-0007 Arm Q

The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm Q is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with HER2 amplification are treated with Kadcyla® (ado-trastuzumab emtansine). This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including tumor tissue and whole blood.

Study phs001926

Structure of the Mucosal and Stool Microbiome in Lynch Syndrome

The gut microbiota has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been elucidated. To prospectively assess microbiome changes prior to colorectal neoplasia, we investigated samples from 100 Lynch syndrome patients using 16S rRNA gene sequencing of colon biopsies, coupled with metagenomic and metatranscriptomic sequencing of feces. Colectomy and CRC history represented the largest effects on microbiome profiles. A subset of Clostridiaceae were depleted in stool corresponding with baseline adenomas, while Desulfovibrio was enriched in both stool and mucosal biopsies. A classifier leveraging stool metatranscriptomes resulted in modest power to predict interval development of preneoplastic colonic adenoma. Predictive transcripts corresponded with a shift in flagellin contributors and oxidative metabolic microenvironment, potentially factors in local CRC pathogenesis. This suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.

Study phs002343

PE-CGS: Optimizing Engagement of Hispanic Colorectal Cancer Patients in Cancer Genomic Characterization Studies

Colorectal Cancer (CRC) is the second leading cause of cancer death in the US. Hispanic/Latinos (H/L) are the largest and fasting growing ethnic group in the US, and cancer is the leading cause of death among H/L in the US. Therefore, we need to fully understand the full complexity of the molecular etiology of cancer in this ethnic group. For instance, although incidence rates of CRC are lower among Latinos as compared to Whites or African Americans, Hispanics with metastatic disease have shorter overall survival when adjusted for health care setting, demographics, disease characteristics and treatment factors. H/L also tend to be diagnosed at a younger age and with higher stage, and we have previously reported that Mexican H/L in California have the greatest proportion of young (The Cancer Genome Atlas has provided a deep overview of the molecular taxonomy of CRC in 594 cases, however, less than 1% of the cases (n=5) were H/L. Therefore, it is imperative for us to take more detailed assessment of the molecular genomic landscape of CRC in H/L. One of the major issues likely limiting our ability to perform these large genomic initiatives in minority patients is that Patient or Participant Engagement practices may not be investigated to identify best practices for accruing and consenting patients into clinical translational biomedical research studies. This concept of Participant Engagement is critically important for both the patients and the translational cancer research community. Optimizing and improving our approaches for directly engaging patients at initial contact, throughout the course of a translational genomic study, and during the time of return of results is likely to lead to stronger relationships between the medical community and patients, but could also lead to significant improvement in outcomes for patients and for the cancer care community as a whole. As such, we propose the creation of the USC Center for Optimization of Participant Engagement in Cancer Characterization (COPECC) with a focus on optimizing the engagement of Latinos in CRC Genomic Characterization research studies. USC COPECC would serve as a member of the NCI U2C Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Our investigative team includes experts in all relevant areas of research for genomic characterization, participant engagement, and engagement optimization. We have an established platform for consenting patients into cancer genomics studies that will serve as a standard process. The overall goal of USC COPECC is to generate results on participant engagement optimization and CRC genomic research that will be shared with the broader community to distribute best practices for engaging Latinos in hopes of improving overall outcomes for CRC in this underserved population.

Study phs003985

Molecular Analysis of Alliance A031201 Study

This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

Study phs003717

Clonal Hematopoiesis Dynamics and Evolutionary Fitness During Breast Cancer Treatment Impact Clinical Outcomes

We investigated the impact of cancer therapies on clonal hematopoiesis (CH), the age-associated expansion of somatically mutated hematopoietic stem cells, in patients with breast cancer. We examined 392 serial peripheral blood samples collected before and after treatment using chemotherapy, radiation, and/or hormone therapy from a prospective cohort of 171 patients. Ultra-deep targeted DNA exon sequencing was performed across 81 genes (custom Agilent SureSelectXTHS2 panel, median coverage > 5000x) implicated in hematologic malignancies and CH, enabling precise characterization of the mutational spectrum and longitudinal tracking of clonal dynamics. The primary objective was to understand how different cancer treatments (i.e., chemotherapy, radiation, and hormone therapy) alter the effective hematopoietic population and select for or against specific CH clones. Our analysis revealed that cytotoxic therapies induced significant reductions in allelic diversity, creating therapeutic bottlenecks that led to selective clonal expansion. These selective dynamics were associated with worse clinical outcomes, where patients with positively selected CH during treatment experienced significantly shorter progression-free and overall survival. Data generated from this study, including the sequencing data, treatment exposure data, and clinical outcomes will be made available through dbGaP. Mutation calls used for analyses are included in the medRxiv (2025.08.27.25334581) supplement and will be available in the published version of the manuscript.

Study phs004283

The Formation and Propagation of Human Robertsonian Chromosomes

Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics have allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level will pave the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.

Study phs003920

Childhood Cancer Data Initiative (CCDI): Whole Genome Landscapes of Patient Derived Osteosarcoma Xenograft Models

Osteosarcoma is the most common primary bone malignancy in children and young adults and has few treatment options. As a result, there has been little improvement in survival outcomes over the past few decades. The need for models to test novel therapies is especially great for this disease because it is both rare and unresponsive to most therapies. To address this need, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been described previously. This study adds whole-genome sequencing (WGS) and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four new osteosarcoma models are described for use by the research community.

Study phs004232

Integrated Somatic and Germline Molecular Properties Dictating Biological and Clinical Phenotypes in Cancer

Study version 1: We performed single-nuclei matched RNA- and ATAC-sequencing of frozen biopsies from normal adjacent tissue, primary and metastatic esophageal adenocarcinoma specimens. The data was then further stratified into a tumor microenvironment and malignant compartment and was computationally analyzed to reveal cancer cell subtypes and programs driving malignancy.Study version 2: We performed single nucleus multiome sequencing (simultaneous ATAC and RNA sequencing) on snap frozen adipose and liposarcoma patient samples.

Study phs003438

Molecular Characterization of the Immunological Landscape in Human Brain Tumors

We are performing a comprehensive cellular and molecular characterization of the immunological landscape of human brain tumors. This work includes single-cell RNA and T cell receptor (TCR) sequencing of T cells isolated from the tumor and blood of patients with advanced primary (high-grade glioma) and metastatic (non-small cell lung cancer) cancers. Whole exome sequencing on tumor and normal tissue was also performed.

Study phs004853

Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

Study phs003511

Spatial Transcriptomics of Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Undergoing Chemotherapy and Radiation Therapy for Stage I or Stage II Pancreatic Cancer That Can Be Removed by Surgery

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Here, spatial transcriptomics data were generated from 16 pancreatic cancer patients treated with GVAX, whose tumors presented with induced intratumoral TLS. Resected tumor specimens were embedded in OCT media and freshly frozen. Sections were cut into 6.5 x 6.5 mm dimensions compatible with Visium spatial transcriptomics slides. TLS-positive tumor sections from 14 patients (14 tumor samples in total) and lymph nodes from remaining patients (2 lymph node samples in total) were selected by an expert pathologist for profiling. We used 4 Visium slides and covered the 16 capture areas with sections cut in a cryostat at 10 µm. The fresh frozen Visium protocol was followed according to manufacturer's recommendations (10x Genomics Spatial 3' v1). Tissue permeabilization and library construction was carried out according to the manufacturer's protocols. Permeabilization time was optimized to 30 minutes. The captured tissue sections were permeabilized to allow RNA to be captured onto the slide where it reverse-transcribed to cDNA. The cDNA was then amplified, and sequencing libraries were prepared using the 10x Genomics Visium Spatial Gene Expression Reagent Kit for Library Preparation. The libraries were then sequenced using an Illumina NovaSeq sequencer. The raw data obtained from the sequencing were processed using the SpaceRanger (spaceranger-1.2.0) pipeline for alignment onto the GRCh38-2020-A reference transcriptome quantification of gene expression. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation.

Study phs003862

Childhood Cancer Data Initiative (CCDI): Identification and Targeting of Treatment Resistant Progenitor Populations in T-cell Acute Lymphoblastic Leukemia

Our goal with this study was to identify the mechanisms of treatment resistance in T-cell acute lymphoblastic leukemia (ALL) using single-cell genomics. We profiled 40 T-ALL cases from the Children's Oncology Group AALL0434 clinical trial using CITE-seq/snATAC-seq, capturing a breadth of immunophenotypes, including early T-cell precursor (ETP) and near-ETP/non-ETP subtypes. By integrating analyses of T-ALL cells with the normal T-cell developmental trajectory, the study identified a specific subgroup of leukemia cells resembling bone marrow progenitors (BMP-like cells). These BMP-like cells were associated with treatment failure and poor overall survival in T-ALL patients. Overall, this study reveals comprehensive multiomic signatures for rapidly assessing risk and tailoring targeted treatment for high-risk T-ALL patients.

Study phs003432

Understanding Determinants of Racial Disparities in Lung Cancer Incidence

This is a nested case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The study included 1258 cases and 1252 controls selected from the Southern Community Cohort Study (SCCS), a large, prospective observational cohort. Cases were identified from cancer registries across the catchment area of the SCCS. Cases and controls were frequency matched on age, sex, race, and enrollment site (community health center vs general population).

Study phs003789

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