Search Results - EGA European Genome-Phenome Archive

Genomic Analysis of Extra-Nodal Natural Killer/T-Cell Lymphoma (ENKTCL)

In this study, we performed extensive genetic profiling on 209 extra-nodal natural killer/T-cell lymphoma (ENKTCL) nasal-type cases, including 174 Chinese from four hospitals in China, and 31 Hispanic and 4 Caucasian patients from City of Hope and Eberhard Karls University of Tübingen. All of the cases were reviewed by experienced hematopathologists to confirm diagnosis. Written informed consents from patients were reviewed and approved by the institutional review board of each institution. We deposited targeted exon sequencing data of a selected 333-gene panel on the ENKTCL cases in dbGaP. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues with an AllPrep DNA/RNA FFPE Kit. A custom platform (Agilent SureSelect) was used to capture target exons from genomic DNA of ENKTCL tumors. DNA was fragmented to 200bp using a Covaris S220 Focused-ultrasonicator and was end-repaired and ligated to Illumina adaptors with a KAPA Hyper Prep Kit. Ligated products were purified and amplified with a 7-cycle PCR. Exome capture from the PCR products was performed using a SureSelect Target Enrichment Kit. The captured exomes were further amplified with an 8-cycle PCR and purified for cluster generation using the cBot cluster generation system with a HiSeq PE Cluster Kit V4. 100bp paired-end reads were generated from an Illumina HiSeq 2500 system with a HiSeq SBS Kit V4.

Study phs002925

CIDR: The Role of Rare Coding Variation in Prostate Cancer in Men of African Ancestry - RESPOND Project 2

In RESPOND Project 2, we seek to identify rare genetic factors that are associated with prostate cancer (PCa) risk and aggressiveness in men of African ancestry (AA). We will conduct exome sequencing of 15,000 prostate cancer cases and 5,000 controls from the RESPOND cohort and the African Ancestry Prostate Cancer Consortium (AAPC) with cases selected based on risk categories: high-risk (stage T3/T4 or Gleason 8+ or PSA>20 ng/ml), intermediate-risk (stage T2b/T2c or Gleason 7 or PSA 10-20 ng/ml) and low-risk disease (stage T1/T2a and Gleason ≤ 6 and PSA<10 ng/ml). We expect the findings from this Project to significantly advance knowledge of susceptibility to aggressive PCa and racial/ethnic disparities in PCa risk, and to guide the development of future preventive, early detection and prognostic measures for AA men. The first phase of the study will include exome sequence data for approximately 7,500 cases and 5,000 controls from AAPC. The second phase of the study will include exome data for 5,000 cases from RESPOND and AAPC.ACKNOWLEDGMENTS and CONTRIBUTING SITES Multiethnic Cohort (MEC): The MEC and the genotyping in this study were supported by National Institutes of Health (NIH) grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Cancer incidence data for the MEC and Los Angeles Study of Aggressive Prostate Cancer (LAAPC) studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with federal funds from the National Cancer Institute (NCI)/NIH/Department of Health and Human Services (DHHS) under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the Centers for Disease Control and Prevention (CDC). Ghana Prostate Study (GPS): The Ghana Prostate Study was funded by the Intramural Program of the NCI/NIH/DHHS under Contract No. HHSN261200800001E. Men of African Descent and Carcinoma of the Prostate (MADCaP): We thank all MADCaP study participants. This work is a product of the MADCaP network. This work was supported by NCI/NIH grant U01CA184374 to Timothy Rebbeck and National Institute of General Medical Sciences (NIGMS) MIRA grant R35GM133727 to Joseph Lachance. Additional funding includes a seed grant from the Integrated Cancer Research Center at Georgia Institute of Technology. UGANDA: The UGANDA study was supported by NIH grant R01CA165862. Southern Community Cohort (SCCS) is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt Ingram Cancer Center (CA68485). Data on SCCS cancer cases were provided by Alabama Statewide Cancer Registry, Kentucky Cancer Registry, Office of Cancer Surveillance at Tennessee Department of Health, Florida Cancer Data System, Central Cancer Registry at North Carolina Division of Public Health, Georgia Comprehensive Cancer Registry, Louisiana Tumor Registry, Mississippi Cancer Registry, South Carolina Central Cancer Registry, Virginia Cancer Registry at Virginia Department of Health, and Cancer Registry at Arkansas Department of Health. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries (NPCR)/Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the NPCR/CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. Karuprostate: The Karuprostate study was supported by the French National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la Prostate. Séverine Ferdinand, Marc Romana. The North Carolina - Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. We would also like to acknowledge the UNC BioSpecimen Facility and the LSUHSC Pathology Lab for our DNA extractions, blood processing, storage and sample disbursement (https://genome.unc.edu/bsp). Gene-Environment Interaction in Prostate Study (GECAP) was supported by NIH grant ES011126. King County Prostate Cancer Study (KCPCS) was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center. We thank the participants in these studies, and Ms. Suzanne Kolb for help with study management. The Los Angeles Study of Aggressive Prostate Cancer (LAAPC) was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI/NIH/DHHS under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the CDC. Prostate Cancer Studies at MD Anderson (MDA) was supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388.

Study phs002637

The Genetic Landscape of Metastasis and Recurrence in Head and Neck Squamous Cell Carcinoma

Recurrence and/or metastasis occur in more than half of patients with head and neck squamous cell carcinoma (HNSCC) and pose the greatest threats to long-term survival. The genetic alterations underlying recurrent/metastatic HNSCC are unknown. This study represents the first whole exome sequencing (WES) cohort study of patient-matched tumor pairs in recurrent or metastatic HNSCC. Synchronous lymph node metastases are genetically more similar to their paired index primary tumors than metachronous recurrent tumors are. Newly arisen mutations in recurrent or metastatic tumors, may have therapeutic implications. Several genes were found to be mutated in multiple metastatic or recurrent tumors, but not in their respective primaries, including C17orf104, ITPR3, and DDR2. DDR2 mutations have been shown to confer enhanced sensitivity to Src-family kinase (SFK) inhibitors in other malignancies. Similarly, we found HNSCC cell lines harboring endogenous and engineered DDR2 mutations to be more sensitive to the SFK inhibitor dasatinib, than those with WT DDR2. This study outlines the first compendium of somatic mutations in primary, metastatic and/or recurrent HNSCC cancers that arise in individual patients; and demonstrates how such data can be used to interrogate potential predictive/prognostic biomarkers to inform and guide personalized therapy.

Study phs001007

Genomic Studies for Understanding Etiology of Esophageal Adenocarcinoma (EsophagealAdenocarcinoma_Chinese)

While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of ten Chinese EAC tumor samples and their matched normals, and compared them to EAC tumor specimens from Western countries previously reported. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of Chinese samples showed evidence of chromothripsis and genome doubling that often found in EAC from Western countries. In summary, Chinese EAC tumor samples revealed distinct genomic profiles and signatures, suggesting that Chinese EAC may arise from a different etiological pathway.

Study phs001696

Multiple Myeloma Genomic Study (MMGS)

Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow (BM) infiltration and lytic bone lesions. Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant clonal heterogeneity in MM. Despite this remarkable clonal heterogeneity, it could be envisioned that such clonal diversity may be even higher since single BM samples only represent a small fraction of the whole BM compartment, and the pattern of BM infiltration in MM is typically patchy. In addition, BM biopsies are painful and cannot be repeated multiple times during the course of therapy, indicating a need for less invasive methods to molecularly characterize MM patients and monitor disease progression during the therapy. Thus, optimal characterization of circulating tumor cells (CTCs) may represent a non-invasive method to capture relevant mutations present in PC clones. In addition, MM almost always progresses from precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) to overt MM. However, some patients rapidly progress from MGUS/SMM to overt MM (progressors) with a rate of progression of up to 70% over 5 years, while others remain indolent with minimal progression over the same time period (non-progressors). Although many patients are diagnosed with earlier phases of disease, most patients do not receive treatment until their disease progresses, at which time they have overt end-organ damage. This concept of initiating therapy at the time of symptomatic disease is analogous to initiating therapy in patients with solid tumors only after the development of measurable metastatic disease. It is therefore not surprising that cure is not achieved for most patients with MM. Interestingly, studies have demonstrated that MGUS/SMM clones may already harbor chromosomal alterations (Ig loci or hyperdiploidy) and that progression to MM is mainly due to expansion of clones that were already present in the early stages of MGUS/SMM. However, the biological factors that discriminate progressors from non-progressors in MGUS/SMM are not well known. Therefore, our overarching hypothesis is that an effective therapeutic intervention will result from defining genomic and transcriptomic markers that are associated with disease progression. We believe, therefore, that focused research studies that define molecular mechanisms of clonal evolution in MGUS/SMM/MM will identify novel biomarkers of disease progression and help develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease. Recently, a new term called Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been proposed to describe asymptomatic individuals with hematologic malignancy-associated somatic mutations. Those individuals do not fulfill any diagnostic criteria for any hematological malignancy yet they have a tendency to progress into myelodysplastic syndrome (MDS) or myeloid or lymphoid neoplasia at a rate of around 0.5-1% per year, similar to MGUS. The frequency of CHIP and role of HSCs mutations in enhancing acquisition of somatic mutations in MM plasma cells, allowing progression following treatment, has not been studied. Investigating the dysregulated pathways in early progenitor cells would allow us to understand the reasons of progression and establish novel therapeutic and potentially preventive strategies. This study dissects genomic and transcriptomic characteristics of clonal evolution from MGUS/SMM to MM as well as the characteristics of the tumor microenvironment/immune cells/peripheral blood. Our hypothesis is that molecular biomarkers will be strong predictors of progression from MGUS/SMM to MM and will allow for the development of novel therapeutic agents that prevent or delay this progression. We aim to define genomic and transcriptomic markers that lead to progression from MGUS/SMM to MM in tumor cells, blood biopsies (cell free DNA and circulating tumor cells), and the tumor microenvironment.

Study phs001323

Genomic Analysis of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a very rare and distinct subtype of hepatocellular carcinoma that occurs in the previously healthy livers of adolescents and young adults. The low incidence rate has kept FL-HCC an understudied cancer, thus the list of FL-HCC markers is limited and the genetic alterations driving its growth have remained unknown. In order to gain a better understanding of the molecular mechanisms underlying FL-HCC initiation and progression, we performed an in-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors. We showed the expression of neuroendocrine markers in FL-HCC. In addition, DNA/RNA sequencing revealed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. Through in vitro studies, we demonstrated the oncogenic properties of these fusion transcripts. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

Study phs000828

Elucidating Transcription Regulation by Epigenetics in Neuroblastoma

PURPOSE Whole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma. PATIENTS AND METHODS Nano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children's Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis. RESULTS Comparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children's Oncology Group cohorts (hazard ratio, 3.8). CONCLUSION 5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype. "Reprinted from Applebaum et. JCO Precision Oncology, 2019, with permission from creative commons license."

Study phs001831

Genomic-Enabled Medicine for Recurrent Glioblastoma

In this prospective study, we performed genome-wide tumor/normal exome sequencing and tumor RNA-sequencing for recurrent glioblastoma patients. A subset of patients had both enhancing tumor and non-enhancing tissue sequenced to investigate spatial heterogeneity of this disease. Together, this information builds our understanding of the genomic underpinnings of glioblastoma, and contributes toward the knowledge base for identifying and developing more effective treatments for patients with glioblastoma.

Study phs001460

National Cancer Institute - Population Structure and Natural Selection in the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study in Uganda

A genome-wide analysis of genetic structure, gene flow, and natural selection was conducted in populations in the endemic Burkitt lymphoma (eBL) belt in Ghana and Northern Uganda, both subject to a high incidence of falciparum malaria and eBL. These populations have different ethnolinguistic ancestries and are located 2400 miles apart in sub-Saharan Africa. We characterized genetic composition of these populations in the context of 22 additional African populations and present evidence for gene flow events that occurred in the last 3000 years, possibly related to regional migrations in Western Africa and major migrations involving Nilotic, Cushitic, and Bantu groups. The Ugandan population was comprised of 758 children (mean age ~7 years) from 17 Western Nilo-Saharan tribes. The current dataset includes 561 healthy children and 197 children with eBL from northern Uganda.

Study phs001705

Subtyping Sub-Saharan Esophageal Squamous Cell Carcinoma by Comprehensive Molecular Analysis

Esophageal squamous cell carcinoma (ESCC) occurs as much as 20x more frequently in sub-Saharan Africa than Western countries. Through the UNC-Malawi project collaboration we obtained whole-exome matched tumor/normal and RNA sequencing of 59 ESCC from Malawi between 2011-2012. DNA analysis revealed similar mutations as other cohorts, while RNA analysis revealed three distinct subtypes. Mutational signature analysis revealed a pattern of mutation not previously reported in other cohorts or more broadly. Taken together this suggests the high prevalence of ESCC in the region is secondary to an as yet identified mutagen.

Study phs001448

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