6048 results for "canc*"

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• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as “likely”, “suspicious for”, “concerning for”, or “favor” metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

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

  The goal of NCI's Pediatric In Vivo Testing Consortium (PIVOT) is to advance the development of effective treatments for pediatric cancers through preclinical in vivo testing of novel therapeutic agents. To design impactful experiments that can be rapidly translated to the clinic, PIVOT investigators require comprehensive genomic characterization of the patient-derived xenograft (PDX) models used across the consortium. This robust experimental design enhances collaboration with industry partners by providing proof-of-concept data for drugs in development. As part of this effort, neuroblastoma PDX models are being molecularly characterized to identify promising therapeutic candidates. The molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Additionally, demographic and clinical data (e.g., diagnosis, disease site, disease status) are shared. These characterized PDX models, matched with patient tumors, guide model selection for preclinical drug testing.

  Study phs003163

• Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer

  This study examined the biological determinants of response to KIF18A inhibition in small-cell lung cancer (SCLC), a chromosomal instability-high cancer. The study used patient tumor datasets, SCLC cell line models, genomic and transcriptomic profiling, drug sensitivity testing, live-cell imaging, genetic perturbation, and pharmacologic inhibition to assess chromosomal instability, mitotic regulation, and spindle assembly checkpoint function. Although KIF18A expression was elevated in SCLC and associated with chromosomal instability, proliferation, and neuroendocrine transcriptional programs, these features did not predict drug sensitivity. Instead, response to KIF18A inhibition was primarily determined by spindle assembly checkpoint competency, with SAC-proficient cells undergoing sustained mitotic arrest and apoptosis and SAC-defective cells showing resistance. The dbGaP-accessible data will include de-identified RNA-seq-derived expression data and associated sample metadata for the NIH/NCI patient-derived SCLC cell line component of the study. These data were used to assess selected gene expression features, including KIF18A-related expression and a neuroendocrine-related score based on Neuroendocrine-associated genes. No direct participant identifiers will be included.

  Study phs004869

• Subtyping of Small Cell Lung Cancer Using ChIP-Seq of Plasma Cell-Free Nucleosomes and Matched Tumor Transcriptomes

  We undertook an observational study using plasma collected from patients with small cell cancer who received care at the National Cancer Institute (NCI). Human subjects committee at NCI approved the studies; all patients provided written informed consent for plasma, tumor, and matched normal sample sequencing. Sequence data for 8 samples in phs003628 are available under phs004200.

  Study phs003628

• Blockade of TGF Beta Drive Hyper Progression on Small Cell Lung Cancer

  To uncover mechanisms underlying divergent outcomes in patients with small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, we performed bulk transcriptomics of pre-treatment tumor biopsies from patients enrolled in a clinical trial of bintrafusp alfa, a bifunctional fusion protein targeting PD-L1 and TGF-β. We identified marked elevation of IFN-γ signaling and MHC class II expression. In contrast, Hyperprogressive disease (HPD) was associated with systemic immune suppression, impaired cytotoxicity, and, unexpectedly, tumor-intrinsic activation of TGF-β signaling and stemness. Functional studies confirmed that intact TGFβR2-mediated signaling is required for the hyperproliferative response to TGF-β blockade, revealing a context-dependent tumor-suppressive role for TGF-β.Although TGF-β is widely regarded as an immunosuppressive driver in advanced cancers, our findings reveal a tumor-intrinsic, growth-constraining role for TGF-β signaling in SCLC. Disrupting this restraint can accelerate tumor progression, providing a mechanistic basis for HPD and highlighting the need for biomarker-driven strategies that account for tumor-intrinsic signaling when applying stromal-targeted immunotherapies.

  Study phs004200

• Whole Genome Sequencing for Metastatic Mutational Burden in Extraskeletal Myxoid Chondrosarcoma

  Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer. Though it has a favorable prognosis and an indolent course, it has high rates of local recurrence and metastasis to the lungs. EMC is most often characterized by a translocation involving the NR4A3 gene most often fusing with EWSR1, leading to constitutive expression of NR4A3, the biological significance of which is unknown. Our study presents a case of EMC with case-matched lung and advanced pelvic metastases. We conducted Whole Genome Sequencing to examine differences in the mutational landscape at two different stages of metastasis. This is the first study to our knowledge to analyze mega-base scale structural variants (SVs) in EMC. Our data validates copy number variants (CNVs) found in previous studies. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. The sequencing data is available through dbGaP.

  Study phs003305

• Childhood Cancer Data Initiative (CCDI): Enhancement of Data Sharing in Pediatric, Adolescent and Young Adult Cancers

  NCI's Childhood Cancer Data Initiative (CCDI) is building a community centered around childhood cancer care and research data. Through enhanced data sharing, we can improve our understanding of cancer biology to improve preventive measures, treatment, quality of life, and survivorship, as well as ensure that researchers learn from every child with cancer. While childhood cancers represent the leading cause of death in children over the age of 1, they are collectively rare, comprising approximately 1%‒3% of cancers diagnosed annually in the United States. Information on diagnosis, treatment, and outcomes is often stored at the hospital or institution where a child is treated, making it difficult to answer scientific questions about childhood cancer. Sharing clinical care and research data generated by children's hospitals, clinics, or networks broadly with the community can help us learn faster and, on a scale much larger than any single institution caring for children can learn on its own. To exploit the rapid advances in high-throughput DNA sequencing technologies and realize the goals of precision cancer medicine, the UMICH Cancer Center established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). This UMICH Cancer Center provisions genomic data derived from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) clinical sequencing assay for patients that fall within the inclusion criteria of the CCDI data sharing initiative. An "integrative sequencing approach" carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. Using a number of computational pipelines that we have developed in-house or have adapted from the public domain, candidate molecular aberrations are nominated and then analyzed by scientists for clinical significance and/or relevance. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant.

  Study phs002431

• GENomics of CAncer DisparitiEs (GENCADE)

  Genetic ancestry-concordant RNA splicing events in men with prostate cancer (PCa) involve cancer promoting genes and associate with disease recurrence after radical prostatectomy. Patients diagnosed with PCa who were scheduled to undergo radical prostatectomy or biopsy were enrolled in the GENCADE study, according to the Institutional Review Board (IRB)-approved protocol Pro00053535 (NCT02229565). With respect to NCT02229565, the descriptors “African American” and “Caucasian American” refer to the same patients described as “Black” and “White”, respectively, herein. Patients were also co-enrolled to the Duke BioRepository & Precision Pathology Center (BRPC) protocol (Pro00035974) to facilitate tissue collection.

  Study phs003731

• Cardiovascular Cell Therapy Research Network - A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors With Anthracycline-Induced Cardiomyopathy (CCTRN-SENECA-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 examine the safety and feasibility of delivering allogeneic human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC).Background: Anthracycline-based chemotherapies are effective in treating various forms of cancer. The risk of anthracycline-induced cardiomyopathy (AIC) has been primarily related to the lifetime cumulative dose and every exposure to an anthracycline carried some risk of inducing cardiac dysfunction. Historically, AIC has been irreversible with poor prognosis and most prevalent in young persons and females. Previous studies have determined that patients with AIC have approximately 3.5-higher relative risk of death within 5 years compared to ischemic or nonischemic cardiomyopathy. There is currently no effective treatment for AIC.There are several shared pathological features between AIC and heart failure (HF). A promising approach to treatment of HF is the administration of bone marrow–derived mesenchymal stromal cells (MSCs). The SENECA trial was the first-in-human study of allo-MSCs in patients with LV dysfunction secondary to AIC.Participants: Male and female cancer survivors aged 18 to 79 years, with a diagnosis of AIC, were recruited for the SENECA trial. Inclusion criteria included: initial diagnosis of AIC at least 6 months prior to consent; left ventricular ejection fraction (LVEF) ≤45%; receiving stable, optimally tolerated therapy with beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and/or aldosterone antagonists unless contraindicated; no evidence of ischemic heart disease; cancer-free for at least 2 years with a low likelihood of recurrence (a 5-year risk of recurrence estimated at ≤30%).Participants were excluded for any condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up.Design: The primary objectives of SENECA were the safety of allo-MSC administration, the feasibility of delivering the cells to the subjects, and collecting outcome measures. The secondary objectives were to determine the effects of allo-MSC administration on LV function and functional status from baseline to 6 months and from baseline to 12 months after treatment.The trial was initiated with a 6-subject, open-label lead-in phase. Between September 2016 and December 2016, 6 candidates consented to participate and received 20 transendocardial, electromechanically-guided injections of allo-MSCs. A complete safety report of the 6 subjects was provided for review by the data safety monitoring board and FDA. Subsequently, the study was allowed to proceed to the randomization phase.Baseline evaluations to determine eligibility included: cardiac magnetic resonance imaging (CMR), 6-min walk test (6MWT), Minnesota Living with Heart Failure Questionnaire (MLHFQ), and a comprehensive laboratory panel that included N-terminal pro-brain natriuretic peptide (NT-proBNP).Between March 2017 and October 2018, 31 eligible subjects were randomized 1:1. There were 14 subjects enrolled in the treatment arm and 17 subjects in the placebo arm. Participants received either 1 × 108 allo-MSCs in 8 ml of Buminate 5% solution or a placebo (8 ml of cell-free Buminate solution) delivered via 20 transendocardial injections (0.4 ml each).All subjects were followed for 1 year, with evaluations at: day 0 (day of injection), day 1, day 7, day 30, day 180, and day 365. A physical examination, electrocardiogram, and laboratory evaluations were conducted at each visit, along with the assessment of adverse events and review of medications. In addition, at 6 months and 1 year, subjects performed the following tests: 6MWT, MLHFQ, and CMR. Serum samples were collected at baseline and 1, 6, and 12 months after treatment to determine whether there were any significant changes in panel reactive antibody (PRA).Conclusions: The SENECA trial demonstrated that allo-MSCs are well-tolerated and that transendocardial injections of allo-MSCs are feasible in patients with AIC. Although the SENECA trial was not designed to test efficacy, a subset of participants was included in secondary endpoint analysis. The only statistically significant differences observed were with the MLHFQ and 6MWT assessments which favored the intervention. Larger studies will be required to determine the efficacy of allo-MSCs treatment.

  Study phs004712

• FORCE Trial: Resistance Training Intervention Among Colon Cancer Patients

  Our study population was composed of participants of the FORCE clinical trial, which was a randomized resistance training intervention study for Stage II and III colon cancer patients undergoing chemotherapy. Patients were recruited from Kaiser Permanente of Northern California, the Penn State Cancer Institute, and the Dana Farber Cancer Institute and were assigned to resistance training or usual care within the first weeks of adjuvant chemotherapy. Lean mass was evaluated at the beginning and the end of the study, and participants were monitored for toxicities associated with chemotherapy and chemotherapy dose modifications. Genome-wide DNA methylation was assayed using peripheral blood collected at the FORCE trial baseline and the post-intervention visit using the Infinium MethylationEPIC v1.0 (EPIC) BeadChips (Illumina). EPIC array signal intensities were preprocessed and used to estimate site-specific DNA methylation levels, which were used for the estimation of several epigenetic clocks. Our study hypothesized that those with accelerated epigenetic age at the beginning of chemotherapy would be more likely to have modifications to their assigned chemotherapy regimen driven by a higher burden of chemotoxicities. We also hypothesized that epigenetic age acceleration would significantly increase over the course of chemotherapy and that a resistance training intervention would reduce the rate of change.

  Study phs003671