Search Results - EGA European Genome-Phenome Archive

RNA-seq of DF149 cells – a patient-derived xenograft model of ascites-derived, homologous recombination repair-proficient, high-grade serous ovarian carcinoma – cultured in vitro and isolated after 8 hours treatment with DMSO control (3 x biological replicates) and 2.5 µM CBL0137 (3 x biological replicates)

Background: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSOCs. Experimental design: We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSOC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSOC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSOC cell lines and patient-derived tumor cells in vitro and in vivo. Results: We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. Conclusion: Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Study EGAS00001006662

Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.

Study EGAS00001006939

NanoString nCounter® PanCancer IO 360™on anti-PD1/anti-PD1+CTLA4 in patients with metastatic melanoma

Patients with advanced melanoma were treated with standard-of-care single agent anti-PD-1 (nivolumab or pembrolizumab) or a combined anti-PD-1+anti-CTLA-4 (ipilimumab) therapy. Patients were retrospectively identified, based on formalin-fixed paraffin-embedded (FFPE) tissue availability. Total RNA was isolated from macro-dissected FFPE tissue sections using the AllPrep DNA/RNA FFPE Kit (Qiagen) or High Pure FFPET RNA Isolation Kit (Roche) according to the manufacturer’s instructions. RNA quantity was assessed on Qubit, and RNA integrity was assessed using the Tapestation system (Agilent). Total RNA samples (60ng/ul, total 200ng) were used as input for the NanoString PanCancer IO360 Panel, run on the nCounter MAX/FLEX prep station and scanner. Samples were hybridised for 20hrs, and each cartridge contained a panel standard.

Study EGAS00001006977

Reprogramming of stroma-derived chemokine networks drives the loss of tissue organization in nodal B cell lymphoma

Here, we utilized single-cell and spatial mapping to interrogate the mechanisms directing tissue architecture in human lymph nodes (LN) and its disruption in nodal B cell lymphoma. Specifically, we mapped the cellular landscape of follicular lymphoma (FL; n=6) and diffuse large B cell lymphoma (DLBCL; n=8) alongside non-malignant reactive LNs (rLN; n=5) using single-cell RNA sequencing. Our data support the central role of LN-resident stromal cells in chemokine-driven lymphocyte zonation and reveal an inflammatory feedback loop fueled by tumor-reactive T cells, triggering stromal remodeling, progressive loss of homeostatic chemokine gradients and tissue organization from non-malignant to FL and DLBCL. Collectively, our results highlight the principles of LN organization and suggest how lymphoma-induced microenvironmental reprogramming drives loss of tissue organization.

Study EGAS00001006986

An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

The bone marrow is continuously occupied by high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. Here, we investigated myeloma-associated alterations in marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor-supportive, transcribing increased levels of pro-inflammatory cytokines, including IL-1β, and myeloma cell survival factors, such as the BCMA-ligand BAFF. Neutrophils were re-activated after first-line treatment, while this regimen reduced, but did not normalize, stromal inflammation. Interactions with inflammatory stroma induced neutrophil activation, including BAFF secretion, in a STAT3-dependent manner and once activated, neutrophils gained the ability to reciprocally induce stromal activation. Combined, our data define the presence of a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that could impact disease recurrence.

Study EGAS00001007038

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Background Liquid biopsies, and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy-number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts, or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.

Study EGAS00001007077

Genome-wide cell-free DNA biological patterns in patients with cancer

The structure of cell-free DNA (cfDNA) is altered in the blood of cancer patients. From whole genome sequencing we retrieved the cfDNA fragment-end composition using a new software (FrEIA), as well as the cfDNA size and tumor fraction in three independent cohorts (n=925 cancer from >10 types and 321 control samples). At 95% specificity, we detect 72% of cancer samples using at least one cfDNA measure, including 64% of early-stage cancer (n=220). cfDNA detection correlates with a shorter overall (p=0.018) and recurrence-free (p=0.006) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n=396 cancer, 90 controls) achieve a detection accuracy of 82% and AUROC of 96%. In conclusion, harnessing the biological features of cfDNA can improve at no-extra cost the diagnostic performance of liquid biopsies.

Study EGAS00001007400

BLUEPRINT September 2016, ChIPmentation Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma from lymph node, on Genome GRCh38

ChIPmentation data for 2 sample(s) Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma from lymph node, on Genome GRCh38. 6 run(s), 6 experiment(s), 6 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002946

Genome and transcriptome sequence data from a metastatic cholangiocarcinoma patient

Genome and transcriptome sequence data from a metastatic cholangiocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

Dataset EGAD00001002976

BLUEPRINT September 2016, RNA-Seq T-cell lymphoma for helper T cell from venous blood, on Genome GRCh38

RNA-Seq data for 2 sample(s) T-cell lymphoma for helper T cell from venous blood, on Genome GRCh38. 2 run(s), 2 experiment(s), 0 alignment(s). Part of BLUEPRINT (September 2016).Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20140811/homo_sapiens/README_rnaseq_analysis_crg_20140811

Dataset EGAD00001002956

4955 results for "*oma"

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Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

NanoString nCounter® PanCancer IO 360™on anti-PD1/anti-PD1+CTLA4 in patients with metastatic melanoma

Reprogramming of stroma-derived chemokine networks drives the loss of tissue organization in nodal B cell lymphoma

An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Genome-wide cell-free DNA biological patterns in patients with cancer

BLUEPRINT September 2016, ChIPmentation Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma from lymph node, on Genome GRCh38

Genome and transcriptome sequence data from a metastatic cholangiocarcinoma patient

BLUEPRINT September 2016, RNA-Seq T-cell lymphoma for helper T cell from venous blood, on Genome GRCh38

Genome and transcriptome sequence data from a rectal adenocarcinoma patient

Genome and transcriptome sequence data from a metastatic gastric adenocarcinoma patient

Genome and transcriptome sequence data from a metastatic neuroendocrine carcinoma of unknown primary patient

Genome and transcriptome sequence data from a metastatic fibrolamellar hepatocelluar carcinoma patient

Genome and transcriptome sequence data from a metastatic pancreatic carcinoma patient

Genome and transcriptome sequence data from a metastatic rectosigmoid adenocarcinoma patient

Genome and transcriptome sequence data from a metastatic carcinoma of the lung patient

Genome and transcriptome sequence data from a metastatic pancreatic carcinoma patient

Genome and transcriptome sequence data from a adenocarcinoma of the lung patient

Genome and transcriptome sequence data from a metastatic endocervical adenocarcinoma patient

Genome and transcriptome sequence data from a cholangiocarcinoma patient

Genome and transcriptome sequence data from a metastatic carcinoma of primary unknown patient

Genome and transcriptome sequence data from a metastatic squamous cell carcinoma of anus patient

Genome and transcriptome sequence data from a carcinosarcoma of the uterus patient

Genome and transcriptome sequence data from a leiomyosarcoma patient

Genome and transcriptome sequence data from a serous carcinoma of fallopian tube patient

Genome and transcriptome sequence data from a glioblastoma multiforme patient

Genome and transcriptome sequence data from a metastatic adenocarcinoma of the lung patient

Genome and transcriptome sequence data from a metastatic adenocarcinoma presumably of ovarian origin patient

Genome and transcriptome sequence data from a metastatic uterine leiomyosarcoma patient

Genome and transcriptome sequence data from a squamous cell carcinoma of the lung patient

Genome and transcriptome sequence data from a metastatic adenocarcinoma of the rectum patient

Genome and transcriptome sequence data from a metastatic ductal carcinoma of the breast patient

Genome and transcriptome sequence data from an ovarian adenocarcinoma patient

Genome and transcriptome sequence data from a chordoma patient

Genome and transcriptome sequence data from a metastatic clear cell sarcoma patient

Genome and transcriptome sequence data from a metastatic uveal melanoma patient

Genome and transcriptome sequence data from a metastatic renal cell carcinoma patient

Genome and transcriptome sequence data from a liposarcoma patient

Genome and transcriptome sequence data from an endometrial adenocarcinoma patient

Genome and transcriptome sequence data from an anaplastic myxopapillary ependymoma patient

Genome and transcriptome sequence data from a pancreatic adenocarcinoma patient

Genome and transcriptome sequence data from a metastatic gastric adenocarcinoma patient

Genome and transcriptome sequence data from a metastatic breast carcinoma patient

Genome and transcriptome sequence data from a breast carcinoma patient

Genome and transcriptome sequence data from a cholangiocarcinoma patient

Genome and transcriptome sequence data from an adrenocortical carcinoma patient

Genome and transcriptome sequence data from a small bowel carcinoma patient

Genome and transcriptome sequence data from a solitary fibrous tumors (sarcoma) patient

Genome and transcriptome sequence data from a liposarcoma patient