Search Results - EGA European Genome-Phenome Archive

Germline Sequence Variation in Cancer Genes Among Rwandan Breast and Prostate Cancer Cases

Inherited genetic information can reduce cancer risk and mortality using protocols for patient ascertainment, testing, counseling, prevention, and treatment. For example, carriers of germline BRCA1/BRCA2 or Lynch Syndrome mutations are at increased risk of breast, ovarian, prostate, endometrial, colorectal, and other cancers. Genetic testing is of clinical value because many mutations are actionable in reducing risk or determining appropriate treatment regimens. There is growing evidence that inherited genetic mutations represent a large proportion of cancer cases in sub-Saharan Africa (SSA). It is also well known that most cancer genetic testing data does not represent the racial and ethnic diversity of the US or global population. Despite the high proportion of cancer cases diagnosed at an early age and late stage, as well as the potential for interventions to reduce cancer risk and death by using genetic tools, genetic testing, counseling, and clinical management protocols have largely not been widely developed in SSA. In order to develop and evaluate the potential for genetic testing in SSA, we propose to undertake a proof of concept feasibility study of hereditary cancer that will contribute data on the prevalence of hereditary cancer mutations in SSA and inform the development of SSA-specific guidelines for cancer genetic testing. In this study, we undertook a pilot evaluation of research genetic testing and counseling in breast and prostate cancer cases in Rwanda that involved genetic testing of breast and prostate cancer cases.

Study phs003927

HINTS Geo-Coded Data 2018 (HINTS 5 Cycle 2)

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 mail-mode data collection cycles over the course of four years. The second round of data collection for HINTS 5 (Cycle 2) was conducted from January 26 through May 2, 2018 with a goal of obtaining 3,500 completed questionnaires. A total of 3,504 respondents are included in the final sample.

Study phs004217

HINTS Geo-Coded Data 2012 (HINTS 4 Cycle 2)

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 second of these cycles (Cycle 2) was conducted from October 2012 through January 2013, including a total of 3,630 respondents.

Study phs004207

A Randomized Phase 2 Study of Cabozantinib in Combination with Nivolumab in Advanced, Recurrent Metastatic Endometrial Cancer

This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial cancer that has come back (recurrent) or spread to other places in the body (advanced or metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and nivolumab may work better in treating endometrial cancer.PRIMARY OBJECTIVE:I. To evaluate the clinical anti-tumor activity of cabozantinib s-malate (XL184 ([cabozantinib]) and nivolumab based on progression free survival (PFS) in patients with advanced, recurrent or metastatic endometrial cancer previously treated with at least one line of platinum-based chemotherapy compared to patients receiving nivolumab alone.SECONDARY OBJECTIVES:I. To evaluate the efficacy of cabozantinib and nivolumab in terms of overall response rate (ORR) compared to nivolumab alone.II. To evaluate overall survival (OS) of patients receiving cabozantinib and nivolumab compared to patients receiving nivolumab alone.III. To evaluate the safety of combination treatment using cabozantinib and nivolumab in patients with advanced, recurrent metastatic endometrial cancer.IV. To evaluate correlation between PD-L1 expression, CD3, CD4 and CD8 infiltrates and outcome (PFS, ORR, OS).V. To compare PD-L1 expression, CD3, CD4 and CD8 infiltrates in the primary tumor (archival tissue) and in the tissue from baseline biopsy.VI. To assess activity (PFS, ORR and OS) of nivolumab alone or in combination with cabozantinib according to microsatellite instability (MSI)/mismatched repair (MMR) status.EXPLORATORY OBJECTIVES:I. To assess activity (PFS, ORR and OS) of XL184 and nivolumab in patients progressed after previous exposure to anti PD-1, PD-L1 or PD-L2 agents or crossed-over from single agent nivolumab, and in patients with diagnosis of carcinosarcoma.II. To compare microsatellite (MS) and MMR status, in the primary tumor (archival tissue) and in the tissue from baseline biopsy.III. To assess the genomic and immune-markers landscape at baseline on tumor tissue and changes in immune landscape in peripheral blood during treatment and correlate with outcome.OUTLINE: Patients are randomized to 1 of 2 arms.ARM A: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.ARM B: Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.In both arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.After completion of study treatment, patients are followed up at 30-37 days, then every 8-12 weeks.

Study phs003414

Derivation of Doxorubicin Mutational Signatures in Cancer

Study design and aims: This study utilizes doxorubicin exposed cell lines to derive doxorubicin mutational signatures. To validate the methodology used (bulk whole-genome sequencing of cells exposed to drug with a pulsed dose-escalation approach), cisplatin mutational signatures are first derived and compared to previously published data (single constant dose of drug and whole-genome sequencing of single-cell clones). The primary aim of the study was to characterize the impact of doxorubicin mutagenesis on the genome. Furthermore, to assess the presence of derived doxorubicin signatures in patient samples treated with a doxorubicin-containing regimen. Population information: The study utilizes atypical teratoid rhabdoid tumor (ATRT) (n=2) and renal medullary carcinoma (RMC) (n=2) cell lines. To acquire cisplatin and doxorubicin exposed cells, parental cells were treated with escalating doses of cisplatin and doxorubicin in a pulsed manner for between 2-12 months. This study also contains 2 cell lines derived from one patient with metastatic disease, treated with a doxorubicin-containing regimen. Molecular technologies: Whole-genome sequencing of the bulk cell population.Principal findings: Cisplatin mutational signatures were consistent with previously published data. This study identified two related single-base substitution (SBS) doxorubicin mutational signatures. While the two resulting signatures had some similarities, they differed in their frequencies of C > A (SBS-Doxorubicin-1) and T > C (SBS-Doxorubicin-2) substitutions. A double-base substitution (DBS) signature was also observed in association with SBS-Doxorubicin-2. This DBS signature harbored peaks at TG > CA, TG > GT, and TT > CC substitutions. Next, two INDEL signatures were derived. The first consisted of 1bp insertions and deletions at T homopolymers, >=2bp insertions at repetitive DNA, and microhomology deletions. The second consisted of >=2bp insertions at non-repetitive regions. Finally, both SBS-Doxorubicin signatures were found to be significantly present in patient samples exposed to a doxorubicin-containing regimen. Data Available through dbGaP: This dataset contains paired-end whole genome sequencing of parental (n=4), cisplatin exposed (n=2), and doxorubicin exposed (n=4) SMARCB1-deficient cell lines, as well as cell lines derived from one patient with metastatic disease (n=2), where the patient was treated with a doxorubicin-containing regimen.

Study phs004740

Identifying and Understanding Drivers of Chemoresistance in Small Cell Lung Cancer

Using patient derived models of small cell lung cancer (SCLC), either the KEAP1 gene or the USP22 gene was deleted using lentiviral expression of a vector expressing CAS9 and single guide RNA (sgRNA) targeting KEAP1 or USP22. Control vector expressing models were also generated. RNA-Seq analysis was performed to compare gene expression in tumors growing in vivo, comparing KEAP1 deleted or USP22 deleted to control tumors under saline-treated and cisplatin/etoposide-treated conditions. Similar experiments were performed overexpressing USP22 or a control vector in a USP22-deleted patient derived xenograft model of SCLC. For USP22-deleted models, we also performed CUT&TAG analyses to examine the impact of USP22 loss on histone modifications.

Study phs004087

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

Long-Read Sequencing of Ovarian Cancer Organoids

Two patient-derived organoids were derived from separate ascites fluid collections from a patient diagnosed with high-grade mullerian carcinoma, that could not be confidently subclassified based on the limited specimen. Long-read sequencing whole genome sequencing (WGS) was performed on the organoids, OC104 and OC109, using the Oxford Nanopore Technologies PromethION24 with V14 ligation kit. Information from genomic findings and further pathology on organoids suggests refining the diagnosis to mucinous ovarian carcinoma.

Study phs004795

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

Childhood Cancer Data Initiative (CCDI): A Cohort of Hispanic Children with Acute Lymphoblastic Leukemia; Bloom Syndrome in a Mexican American Family with Rhabdomyosarcoma

Retrospective case-control genetic study of Hispanic children with acute lymphoblastic leukemia (ALL) treated 1994-2013, comparing 14 treatment-related pancreatitis (TRP) cases to 46 treatment-matched controls without pancreatitis. Targeted sequencing of 23 genes (pancreatitis-related and asparagine-metabolism genes) was performed from post-remission blood DNA; select HLA types were inferred from whole-exome data in cases. CFTR and ASNS variants were enriched in TRP (notably CFTR V470M, OR 4.27, p=0.025).

Study phs002823

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