6048 results for "canc*"

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• HiDEF-seq Single-Molecule Sequencing of Single-Strand Mismatches and Damage

  Our study sought to resolve, with single-molecule resolution, the mismatches and damage events that precede DNA mutations. Using a novel single-molecule, long-read sequencing method (HiDEF-seq) we detected base substitutions when present in either one or both DNA strands. We compared the fidelity for dsDNA mutations to that of the same samples profiled by NanoSeq duplex sequencing. We also detected cytosine deamination, a common type of DNA damage, with single-molecule resolution. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes. These samples revealed single-strand mismatch and damage signatures. Since double-strand DNA mutations are only the endpoint of the mutation process, our approach enables new studies of how mutations arise in a variety of contexts, especially in cancer and aging.The data available via dbGaP includes raw HiDEF-seq sequencing files (Pacific Biosciences subreads in BAM format), raw NanoSeq sequencing files (Illumina FASTQ format), and raw germline sequencing files (Illumina FASTQ format).The HiDEF-seq main publication contains a supplementary table with a list of accession IDs for each sample's files.

  Study phs003604

• Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to the Antibody Drug Conjugate Sacituzumab Govitecan

  Sacituzumab Govitecan (SG), a novel antibody drug conjugate (ADC) incorporating the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 inhibitor (SN-38) payload, is the first ADC to be approved for advanced triple negative breast cancer (TNBC). However, mechanisms governing therapeutic resistance to SG are not known. We sought to identify mechanisms of de novo and acquired resistance to SG through unbiased whole-exome sequencing (WES) and RNA sequencing analysis of pre-treatment and multi-site post-progression (autopsy) tumor specimens. We examined three metastatic TNBC cases exhibiting (1) de novo progression, (2) stable disease, and (3) a deep response followed by progression, then mapped the temporal and spatial genomic evolution of acquired resistance in the responding patient. We then conducted additional pre-clinical experiments to validate the observed resistance mechanisms. TROP2 RNA and gene copy number were associated with de novo resistance, as case (1) was found to have absent TROP2 expression in all specimens, case (2) expressed TROP2, while case (3) exhibited both expression and focal genomic amplification of the TACSTD2/TROP2 locus. The genomic phylogeny tree inferred from case (3) post-progression specimens revealed one branch harboring an acquired canonical E418K resistance mutation in TOP1 (encoding topoisomerase 1) and a subsequent sub-clonal TOP1 inactivating frameshift mutation, while a distinct branch exhibited acquisition of a novel T256R missense mutation in TACSTD2 (encoding TROP2). Both the TOP1- and TACSTD2-mutant clones seeded multiple distinct metastatic sites. Through reconstitution experiments in TROP2 negative cells we found that TROP2 T256R is a stable protein with defective cell membrane localization and reduced cell surface binding by RS7 compared to wild-type TROP2. Collectively, these findings underscore TROP2 as a determinant of initial response to SG, and they reveal parallel and mutually exclusive polyclonal molecular mechanisms of acquired resistance involving the direct antibody target and drug payload target in distinct metastatic subclones of a single patient. While further research is needed to extend these novel findings, this study highlights the specificity of SG and illustrates how identifying such mechanisms will inform rational therapeutic strategies to overcome ADC resistance.  

  Study phs002555

• The Oral Mycobiome and Risk of Pancreatic Cancer

  The purpose of our study was to assess the influence of oral microbiota on the development of pancreatic cancer. Our preliminary case-control studies showed that oral carriage of a periodontal pathogen is related to increased risk for pancreatic cancer. We hypothesize that the oral bacteria and fungi are associated with risk of pancreatic cancer. We conducted a prospective study nested in two large well-established U.S. cohorts to determine whether the oral bacterial and fungal microbiome is associated with subsequent risk of pancreatic cancer.

  Study phs003994

• Bulk ATAC and RNA Sequencing of Human Breast Cancer Metastasis Samples

  Bulk RNA-Seq and ATAC-Seq were performed on a number of matched primary breast and metastatic lung/liver tissues; in addition, non-matched metastases and primaries were also sequenced. The goal of this study is to better understand the role that regulatory elements, such as enhancers, play in metastatic breast cancer.

  Study phs003363

• Blood and Marrow Transplant Clinical Trials Network - A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN-1703-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 compare two graft-vs.-host-disease prophylaxis strategies in patients undergoing hematopoietic stem cell transplantation after reduced-intensity conditioning.Background: The combination of methotrexate and a calcineurin inhibitor has been the standard of care for graft-vs.-host disease (GVHD) prevention in patients undergoing allogeneic transplantation. However, acute GVHD, chronic GVHD, or both develop in more than half of these patients, resulting in complications and death.In 2013, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) launched a phase 2 clinical trial (BMT CTN 1203) comparing three different GVHD prophylaxis strategies with a contemporaneous control regimen of tacrolimus/methotrexate (Tac/MTX) in patients undergoing hematopoietic stem cell transplantation (HSCT) after reduced-intensity conditioning (RIC). That trial identified the combination of cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as the most promising regimen. BMT CTN 1703 was a phase 3 follow up study initiated to compare PTCy/Tac/MMF to Tac/MTX.Participants: Eligible participants were aged 18 years or older and undergoing their first allogeneic transplantation. Eligible diagnoses included: acute leukemia or chronic myeloid leukemia with no circulating blasts and less than 5% blasts in the bone marrow or myelodysplasia or chronic myelomonocytic leukemia with no circulating blasts and fewer than 10% blasts in the bone marrow, chronic lymphocytic leukemia or small lymphocytic lymphoma, or lymphomas that were sensitive to therapy.A total of 431 participants were enrolled and underwent randomization. 214 participants were assigned to receive experimental prophylaxis and 217 participants were assigned to receive standard prophylaxis.Design: The BMT-CTN 1703 study was a randomized, multicenter Phase 3 clinical trial. Participants with hematologic cancers were randomly assigned in a 1:1 ratio to receive PTCy/Tac/MMF (experimental prophylaxis) or Tac/MTX (standard prophylaxis). The participants underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning.The experimental prophylaxis regimen consisted of the following: cyclophosphamide (50 mg per kilogram per day on days 3 and 4 after HSCT); tacrolimus starting on day 5 (orally at a dose of 0.05 to 0.06 mg per kilogram per day or intravenously at a dose of 0.02 to 0.03 mg per kilogram per day; taper could start on day 90 with a goal of discontinuation by day 180); and mycophenolate mofetil (15 mg per kilogram per dose orally or intravenously), not to exceed 1 g thrice daily, starting on day 5 to day 35. The standard-prophylaxis regimen consisted of methotrexate (an intravenous bolus of 15 mg per square meter on day 1 and an intravenous bolus of 10 mg per square meter on days 3, 6, and 11) and tacrolimus (dose as above, starting 3 days before HSCT; taper could start on day 90 with a goal of discontinuation by day 180).The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause.Conclusions: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide/tacrolimus/mycophenolate mofetil than among those who received tacrolimus/methotrexate.

  Study phs004711

• Childhood Cancer Data Initiative (CCDI): Metastatic Osteosarcoma Spatial Profiling

  This study contains spatial transcriptional profiling of metastatic osteosarcoma specimens using the Visium platform. This work was done as part of the Childhood Cancer Data Initiative (CCDI).

  Study phs003975

• Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-Based Cohorts (LEANORA)

  Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan microarray. CYP3A5*3, CYP3A5*6, and CYP3A5*7 variants were genotyped and CYP3A5 phenotypes were constructed from these data. We observed 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve of plasma concentration versus time curve (AUC) of ribociclib did not differ between PMs (39,230 hr*ng/mL) and IM/NMs (43,546 hr*ng/mL; P=0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.

  Study phs003770

• Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration

  The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. We used continuous long-read sequencing of oropharyngeal cancers and cervical cancer cell lines to resolve structural variation induced by HPV. We discovered a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer.

  Study phs003396

• NCTN: EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study (S0931)

  Study ID: S0931 NCT Number: NCT01120249 SWOG Cancer Research Network Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, a Phase III Study (S0931) Trial Description: RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. PURPOSE: This phase III trial is studying everolimus to see how well it works in treating patients with kidney cancer who have undergone surgery. Clinical data presented in the following publication(s): PMID 37524096 Disease type(s): Kidney Neoplasm - Renal Cell Carcinoma Clinical Dataset(s) included: NCT01120249-D1 (PMID 37524096): There are two datasets for S0931's primary publication 37524096 (-D1 and -D2). The clinical dataset contains patient-level data (one row per patient), including eligibility, evaluability, treatment, demographic, baseline information, stratification factors, and unblinding. It also contains survival, cause of death, recurrence site, biopsy, and dose modification data. NCT01120249-D2 (PMID 37524096): There are two datasets for S0931's primary publication 37524096 (-D1 and -D2). This toxicity dataset contains event-level information (one row per patient per adverse event experience on trial). 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 phs004249

• Germline Mutations and Developmental Mosaicism Underlying EGFR-Mutant Lung Cancer

  We designed this study to examine the etiology of multiple lung tumors in EGFR-mutant non-small cell lung cancer patients who undergo surgical resection. Participants were 52-85 years old never or former smokers, who had at least 2 surgical lung tumor pathology specimens available in the Massachusetts General Hospital biobank, at least one of which had an EGFR mutation by routine clinical genotyping. 10 patients were selected, along with two patients from a family with an inherited EGFR-T790M mutation leading to multiple lung tumors. These patient tumor samples and matched normal lung samples were microdissected to collect DNA.In addition to obtaining clinical histories, we performed whole exome sequencing to evaluate the genetic profile of matched tumor and normal samples. The WES data are available on dbGaP. Our data showed increasing mutational burden and copy number alteration with increasing invasiveness, as compared to normal tissues, for the subset of samples that were assessed for tumor invasiveness. We also observed a range of numbers of shared mutations between tumors in a single patient, indicating different degrees of relatedness between lung tumors. We hope that this resource will help researchers understand non-small cell lung cancer presentations with multiple lung tumors. These data may aid in clinical decision making for such patients.

  Study phs003379