3772 results for "*oma"

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• International Cancer Proteogenome Consortium (ICPC): proteogenomics of early stage lung adenocarcinoma in Taiwan

  Lung cancer in East Asia is characterized by high percentage of never-smokers, early-onset and predominant EGFR mutations. To provide an insight into the molecular phenotype of this demographically distinct disease, we have performed a proteogenomics study on a prospectively collected cohort representing early stage lung adenocarcinomas in Taiwan. The distinct mutational profile revealed high prevalence of the APOBEC mutational signature in early-onset females implicating differential regulation of APOBEC enzymes and DNA damage pathways, as well as enrichment of mutational signatures congruent with environmental carcinogens over-represented in the genomic location of EGFR. We delineate the proteogenomic hallmarks of tumor progression and propose a proteomics-informed classification that resolves the EGFR mutation heterogeneity associated with survival within the early stages. Functional annotation of the molecular subtypes by protein network analysis highlights candidate biomarkers for patient stratification. Our integrative analysis reveals the molecular architecture of lung cancer in East Asia and enables the path for precision medicine.

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• National Cancer Institute Clinical and Laboratory Analysis of Familial Cancer

  The purpose of this study is to continue the analysis begun on 09C0079 which was focused on identification of the genetic mutation associated with a new gastric polyposis syndrome, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). GAPPS, first described in 2012, is an autosomal dominant gastric polyposis syndrome that confers a substantial risk for gastric adenocarcinoma. The GAPPS phenotype consists of a carpeting of greater than 100 fundic gland polyps (FGPs) in the oxyntic mucosa of the gastric body and fundus, with antral sparing with some FGPs displaying high-grade dysplasia. This is in contrast to sporadic FGPs that are benign, most often are not associated with high-grade dysplasia though low-grade dysplasia has been reported, and are fewer in number. Gastric FGPs have been found to be associated with Familial Adenomatous Polyposis (FAP) and attenuated FAP, which is an autosomal dominant condition associated with germ line mutations in APC which confers a phenotype consisting of multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. FGPs are reported to occur in 12-84% of patients with FAP, whereas sporadic FGPs are identified in ~5% of patients undergoing upper gastrointestinal endoscopy. Gastric adenocarcinoma arising from FGPs in individuals with FAP have been reported. Other manifestations of FAP and AFAP include polyps in the upper gastrointestinal tract, congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignancies such as thyroid, small bowel cancer, hepatoblastoma, and medulloblastoma. Thus far there are no reports in GAPPS of polyposis arising in the esophagus, gastric antrum, pylorus, small intestine, or colon.

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• NIDCD Otitis Media Genetic Susceptibility and Middle Ear Microbial Shifts

  The study funded by R01 DC015004 aims to: (1) Identify rare OM susceptibility variants within families and in probands; and (2) Identify differences in the middle ear microbiome due to OM susceptibility variants. This study will also elucidate mechanisms responsible for the formation and growth of cholesteatoma, and bony erosion and complications due to cholesteatoma e.g. intracranial, hearing/vestibular loss, facial nerve palsy. A better understanding of cholesteatoma pathogenesis will potentially reveal novel drug targets, which can lead to new non-surgical therapies for cholesteatomatous OM. Our specific aims for this administrative supplement are: Aim 1 -- Perform RNA-sequencing using cholesteatoma samples collected from Filipino and Colorado patients who will be screened for FUT2, SPINK5 and A2ML1 variants; and Aim 2 -- Using network analysis, identify bone-expressed proteins potentially interacting with FUT2, SPINK5 or A2ML1, then test protein expression in archival human temporal bone in direct contact with cholesteatoma.

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• Molecular Genetics of Secondary Histiocytic/Dendritic Sarcoma

  This is a comprehensive genomic analysis of a rare set of secondary histiocytic/dendritic sarcomas from the consult service of the Hematopathology section of the Laboratory of Pathology, NCI, NIH.

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• Hereditary Cancer Predisposition Syndromes and Uveal Melanoma

  Uveal melanoma (UM) is a subtype of melanoma characterized by the strong contribution of genetic rather than environmental factors in the pathogenesis of the disease, making it an ideal model disease to study the genetic basis of cancer. The long-term goal of our laboratory is to determine the genes and mechanisms responsible for hereditary cancer predisposition associated with UM. BAP1 has been identified as a candidate gene with definitive association with predisposition to UM. However, pathogenic variants in BAP1 are detected in only a small subset of UM patients even those with strong personal and family history of cancer suggesting the existence of other candidate genes. The goal of this project is to identify novel candidate genes contributing to hereditary predisposition to UM in patients with no detectable germline pathogenic variant in BAP1.

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• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

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• Genomic profiling for metastatic uveal melanoma from a phase I study of the protein kinase C inhibitor AEB071

  Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Metastatic UM patients (n=153) were treated with AEB071 in a Phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1400 mg. First-cycle dose-limiting toxicities (DLTs) were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses > 700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing (NGS) was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of PKC inhibitors with other compounds in metastatic UM.

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• Genomic Profiling of Peripheral T-cell Lymphoma

  Peripheral T-cell lymphomas (PTCLs) are malignant and highly aggressive hematologic tumors arising from mature post-thymic T cells. The diagnosis of PTCL includes diverse lymphoma subgroups, altogether accounting for about 15% of all non-Hodgkin lymphomas. Despite recent advances in uncovering the mutational landscape of PTCLs, the prognoses of most PTCLs remain poor. To overcome the limits of exome sequencing and identify new genomic abnormalities in PTCL, we performed RNAseq and whole genome sequencing. From our analyses, we identified a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7). These genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support an oncogenic role for VAV1 signaling in the pathogenesis of PTCL (Abate et al., 2017). Recently, we have also identified a novel chimeric oncogene, FYN-TRAF3IP2, in the RNA-seq and whole genome sequencing analyses. FYN-TRAF3IP2 leads to aberrant NF-κβ activity downstream of T-cell receptor signaling and induces NF-κβ-driven T-cell transformation when expressed in hematopoietic progenitors in mice. This novel gene fusion supports the oncogenic driver role of NF-κβ signaling in the pathogenesis of PTCL (Kim et al., in review).

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• Molecular Biomarkers in Glioma (Mechanisms and Therapeutic Implications of Hypermutation in Gliomas)

  This study seeks to genomically and mechanistically examine the basis for resistance of glioblastoma to chemotherapy, radiation therapy, and targeted therapy including immunotherapies. The study design addresses two Aims. In Aim 1, we will test the hypothesis that treatment with radiation and temozolomide or other therapies leads to consistent genetic changes in human tumors using whole exome sequencing of paired pre- and post-treatment tumor samples to determine large-scale changes in population structures and single cell whole genome sequencing to evaluate the effects of these treatments on microheterogeneity. In Aim 2, we will test the hypothesis that genetic changes identified in post-treatment glioblastomas (GBMs) functionally contribute to various forms of resistance in GBM using patient derived cell lines (PDCL) and patient derived xenografts (PDX). These studies will create a comprehensive understanding of genetic evolution during standard-of-care therapy for GBM. They will inform diagnostic approaches for assignment of targeted therapeutics in the recurrent setting and identify genetic changes driving resistance. Therapeutic targeting of these novel resistance drivers could represent a rational approach to substantially improve our existing standard of care for GBM patients.

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• Cellular Origins and Genetic Landscape of Cutaneous GD T Cell Lymphoma

  Cutaneous gamma-delta T cell lymphomas are a rare and aggressive subtype of cutaneous lymphoma. In the present study, we analyzed these cancers by DNA and RNA sequencing in order to illuminate the genetic landscape for this rare disease. We obtained tumor samples from multiple institutions, including Northwestern University (Chicago, IL), University of Chicago (Chicago, IL), University of Virginia (Charlottesville, VA), and Massachusetts General Hospital (Boston, MA).

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