3794 results for "*oma"

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• Whole_Exome_PC9_and_A375

  Drug resistant population of PC9(human non-small cell lung cancer) or A375 (human melanoma) cell lines were used for this study. By exome sequencing, we will analyse mutations of cells in drug tolerent state and after drug holiday.

  Study EGAS00001002493

• Defective Homologous Recombination DNA Repair as Therapeutic Target in Advanced-Stage Chordoma (HIPO_021)

  HIPO project: HIPO_021 Importance: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown.Objective: To identify therapeutically tractable genetic lesions in a cohort of chordoma patients within a genomics-guided precision oncology program and to document the outcome of individualized, molecularly targeted chordoma therapy.Design, Setting, and Participants: We performed whole-exome sequencing of tumor and matched germline control samples from seven patients with locally advanced or metastatic chordoma who were enrolled in a cross-institutional molecular stratification registry trial for younger adults with advanced-stage cancer across all histologies and patients with rare tumors. All patients were heavily pretreated and had progressive disease prior to molecular analysis.Interventions: Individualized medical therapy was administered according to the patients’ molecular profiles.Main Outcomes and Measures: Candidate therapeutic targets identified by whole-exome sequencing and response to genotype-directed therapy.Results: All patients harbored alterations of two or more genes known to be involved in DNA repair via homologous recombination (HR), including heterozygous deletions of ERCC6, FANC family members, RAD51L (n = 6), BRCA2 (n = 5), ATR, CHEK2, RAD18, RAD51B, and XRCC3 (n = 4); inactivating PTEN mutations coupled with loss of heterozygosity (n = 2); and pathogenic germline variants in BRCA2 (n = 1), NBN (n = 1), and CHEK2 (n = 1) that were accompanied by somatic deletion of the corresponding wild-type alleles. Consistently, a mutational signature associated with defective HR was enriched in all samples and co-occurred with extensive genomic instability, as evidenced by HR deficiency scores and high numbers of large-scale state transitions. These results prompted off-label treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient whose tumor was refractory to irradiation and systemic treatment with imatinib, which led to a prolonged response and substantial clinical improvement.Conclusions and Relevance: Advanced-stage chordomas are frequently characterized by genomic imprints of defective HR DNA repair. HR deficiency represents a new therapeutic opportunity in this intractable disease through repositioning of PARP inhibitors that warrants further exploration in clinical trials.

  Study EGAS00001002720

• We describe a method to culture organoids from adult human kidney tissue and describe applications for the culture system.

  Adult Stem Cell (ASC)-derived organoids are 3D epithelial structures that recapitulate essential aspects of their organ of origin. We have developed conditions for the long-term growth of primary kidney epithelial organoids. Cultures can be established from mouse and human kidney tissue, as well as from urine and can be expanded for at least 20 passages (> 6 months). Chromosome numbers remain normal. Human organoids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. BK virus infection of organoids recapitulates in vivo phenomena. Organoids can be established from Wilms nephroblastoma. Kidney organoids from Cystic Fibrosis (CF) patient’s urine allowed ex vivo assessment of treatment efficacy. Finally, organoids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active transport function. Adult kidney-derived organoids allow studies of hereditary, infectious and malignant kidney disease in a personalized fashion.

  Study EGAS00001002729

• NRG1 Fusions in KRAS Wild-type Pancreatic Cancer (H021)

  We used whole-genome and transcriptome sequencing to identify clinically actionable gene fusions in young adults with KRAS wild-type (KRASwt) pancreatic ductal adenocarcinoma (PDAC). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in two patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASwt tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of PDAC patients.

  Study EGAS00001002759

• Predictor_ChemoNEAR_TNBC

  In this study a collection of core biopsies from breast cancer patients receiving neoadjuvant chemotherapy as part of the ChemoNEAR trial will be investigated. The study is intended to detect early acquired resistance in women with diagnosed breast carcinoma. Samples will undergo whole genome sequencing and analysis, including use of HR Predict.

  Study EGAS00001002806

• The genomic landscape of germinal center derived B-cell lymphomas other than follicular, diffuse-large B-cell and Burkitt lymphom

  As part of the ICGC, the ICGC MMML-Seq project performed whole genome sequencing and RNA sequencing of germinal center derived B-cell lymphoma. Analyses were performed in concordance with the guidelines of the ICGC.

  Study EGAS00001002422

• Cell fate mapping of human glioblastoma reveals an invariant stem cell hierarchy pre- and post-treatment

  Human glioblastomas (GBMs) are thought to harbour a subpopulation of glioblastoma stem cells (GSCs) that initiate tumour formation and regrowth following treatment. However, the origin of their proliferative heterogeneity during tumour growth pre- and post-treatment remains poorly understood. Here we study the clonal evolution of DNA barcoded GBMs following their serial propagation in xenograft mouse models to define the fate behaviour of individual GBM cells. Through quantitative analysis of clone sizes scored across multiple passages, we show that the growth of GBM clones in vivo are consistent with a remarkably neutral process resulting from a conserved proliferative hierarchy. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, that in turn generates short-lived cells that lack proliferative ability. We also identify rare "outlier" clones that deviate from these dynamics, and further show that chemotherapy reproducibly facilitates the selective expansion of pre-existing drug-resistant GBM lineages. Finally, we show that coexisting, functionally distinct GSCs may be targeted separately with epigenetic compounds. These findings show that, independent of an evolving mutational signature, the clonal dynamics of human GBM can be surprisingly robust, with intratumoural heterogeneity derived primarily from the defined stochastic fate behaviour of tumour cells within a conserved proliferative hierarchy.

  Study EGAS00001002424

• Integrative genomic and transcriptomic analysis of adult leiomyosarcoma (HIPO-028, HIPO-018, HIPO-021)

  Leiomyosarcoma (LMS) is an aggressive mesenchmyal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. We performed genomic and transcriptomic profiling of a large cohort of LMS tumors and identified substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations, chromothripsis, and frequent whole-genome duplication. Furthermore, we discovered recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and RPA1, resulting in alternative lengthening of telomeres in 78% of cases. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in various homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin treatment. This first comprehensive study of genetic alterations in LMS has uncovered key biological features that may inform future experimental research and enable the design of novel therapeutic strategies for this disease.

  Study EGAS00001002437

• Successful immune checkpoint blockade in a patient with advanced stage microsatellite unstable biliary tract cancer (H021)

  Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host’s immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-year old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient’s tumor displayed DNA mismatch repair deficiency and microsatellite instability (MSI), but lacked other features commonly discussed as predictors of response towards checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor’s antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade. (H021)

  Study EGAS00001002441

• Genetic Risk for Subsequent Neoplasms among Long-term Survivors of Childhood Cancer in the St. Jude Lifetime Cohort

  While childhood cancer survivors are known to be at increased risk of subsequent neoplasms (SNs), the contribution of germline mutations in cancer predisposition genes to the risk of SN is largely unknown. Whole-genome sequencing (30X) was performed on 3,006 5+ year survivors of childhood cancer (median age, 35.8 [range: 7.1-69.8] years) from the St. Jude Lifetime Cohort. Survivors underwent a comprehensive clinical assessment. Germline mutations in 156 cancer predisposition genes (SJCPG156), including a subset of 60 (SJCPG60) autosomal dominant genes with moderate to high penetrance, were classified for their pathogenicity. Piecewise exponential regression, stratified by radiation exposure, was used to evaluate the relative rate (RR) and 95% confidence interval (95% CI) of SN occurrence by mutation status. Pathogenic or likely pathogenic mutations in SJCPG156 and SJCPG60 were identified in 11.7% and 5.8% of survivors, respectively. The most frequently mutated SJCPG60 genes included RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12) and TP53 (n=10). Mutations in SJCPG60 were associated with the rate of subsequent sarcoma (RR, 10.3; 95% CI, 4.2 to 25.6) and breast cancer (RR, 13.3; 95% CI, 5.8 to 30.5) among irradiated survivors, and the rate of developing any SN (RR, 4.8; 95% CI, 2.4 to 9.4) and breast cancer (RR, 7.8; 95% CI, 2.5 to 24.0) among non-irradiated survivors. The rate of developing ≥2 histologically distinct SNs was increased 17.8-fold (95% CI, 3.5 to 89.8) among SJCPG60 mutation carriers treated without radiotherapy. Similar but attenuated associations were observed for mutations in SJCPG156. Survivors who develop a SN without prior radiotherapy or who are diagnosed with a subsequent sarcoma or breast cancer within a site of prior radiotherapy should be referred to genetic counseling.

  Study EGAS00001002499