8255 results for "canc*"

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• Functional screening on patient-derived organoids identifies a therapeutic bispecific antibody that triggers EGFR degradation in LGR5+ tumor cells

  Patient-derived organoids (PDOs) have demonstrated predictive value in prospective clinical trials supporting selection of personalized treatments. Because PDOs retain the organization and physiological functions of their source tissue, PDO biobanks could also be an ideal substrate to screen for novel therapeutic interventions. Here we describe a large-scale functional screen of dual targeting bispecific antibodies (bAbs) on a colorectal cancer (CRC) PDO biobank to target their dependency on cancer stem cells. A novel drug discovery pipeline was assembled where therapeutic bAb panels generated against WNT and receptor tyrosine kinases (RTK) targets were functionally evaluated by high content imaging to capture the complexity of PDO responses across a wide range of different CRCs and paired normal colonic mucosa samples. Our strategy resulted in a bAb that specifically triggers EGFR degradation in LGR5+ CSCs and that exhibits unique therapeutic properties such as potent growth inhibition of KRAS mutant CRCs, blockade of metastasis initiation in preclinical models and minimal toxicity towards normal LGR5+ colon stem cells.

  Study EGAS00001004584

• Understanding_the_multicellular_dynamics_of_clear_cell_renal_cell_carcinoma___visium

  This study will reconstruct the single cellular phylogeny of tumour and immune cells in relation to both genomic, functional, and spatial location. 20 tumours in total will be studied, including non-progressing small renal masses, progressing small renal masses, relatively indolent larger tumours, and high risk tumour with metastatic sampling. We aim to: Generate a focused, comprehensive phylogenetic characterisation of tumour cells Understand the dependencies of the cancer genome, transcriptome, tissue architecture and the single cellular micro-environment Quantify the single cellular composition and functional intra- and inter- tumoural heterogeneity Determine the phylogeny of tumour associated lymphocytes and their relationship to neo-epitopes and the immune microenvironment Investigate the mechanisms by which the tumour-normal interface constrains tumoural growth.

  Study EGAS00001006045

• WGS of gastric cancer in the Japanese population (81 gastric cancers of NCC)

  As a contribution to The International Cancer Genome Consortium Accelerating Research in Genomic Oncology (ICGC ARGO), whole-genome sequencing of 81 cases from Japanese gastric cancer with various histological subtypes has been conducted. This study aims to reveal the landscape of structural variants (SV) in gastric cancer and analyze mutational and rearrangement signatures simultaneously

  Study EGAS00001006051

• Patient-tailored design for selective co-inhibition of leukemic cell subpopulations

  The extensive primary and secondary drug resistance in many cancer types requires rational approaches to design personalized and selective combinatorial therapies that do not only show synergistic effect in overall cancer cell killing but also result in minimal toxic side effects on non-malignant cells. To address the combinatorial explosion in the number of relevant combinations, we implemented a machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA-sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory AML patient cases, each with a different genetic background, our integrated approach accurately predicted patient-specific combinations that were shown to result not only in synergistic cancer cell co-inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our data-driven approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of non-malignant cells, and highlight the relevance of considering cell heterogeneity for personalized cancer therapy.

  Study EGAS00001004614

• Germline variants in patients with rare cancers and their implications for precision cancer medicine: experiences from the Multicenter MASTER Trial by the German Cancer Consortium (HIPO_021)

  The era of precision oncology entails an increasing amount of molecular data from tumor sequencing in research and diagnostics. In this setting, germline variant analysis may add clinical benefits for patients and family members. In this study, we evaluated germline variants from genome/exome matched tumor-blood sequencing in 1.485 advanced cancer patients within a prospective observational study carried out by the German Cancer Consortium. Included patients had cancers of rare entities (79.2%) or were under the age of 51 at first diagnosis (76.6%). Ten percent of the patients harbored pathogenic germline variants in 35 tumor predisposition genes with autosomal-dominant inheritance such as BRCA1, BRCA2, TP53, RB1, CHEK2, ATM, PALB2, SDHB etc., while 4.6% of the patients were carriers of pathogenic germline variants in 18 genes with autosomal-recessive inheritance of tumor predisposition. Based on pathogenic germline variants, 14% of the patients received genetic counselling recommendations in the molecular tumor board report. Forty five percent of pathogenic germline variants supported a molecular treatment recommendation, which was implemented for 28 patients. Furthermore, we compared our approach and results to previous studies, broadening the insight into pan cancer germline findings but also revealing differences between studies on various levels, such as cohort demographics, tumor entities, gene nominations, variant detection and variant interpretation. Our data support the importance of germline variant interpretation in precision oncology studies for patients and their families, if applicable. However, guidelines for evaluation and reporting of germline variants in the context of genetic tumor profiling need to be established and further research on the relevance of germline mutations as biomarkers for treatment recommendations is needed.

  Study EGAS00001005537

• Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocarcinogenesis

  Infection by Hepatitis B Virus (HBV) is the main risk factor for Hepatocellular Carcinoma (HCC) worldwide. HBV can directly drive carcinogenesis through integrations in human genome. This integrative analysis of a French cohort of 190 patients mainly coming from Europe and Africa provides a deep characterization of HBV integrations, in relation with viral and host genomics and clinical features. Clonal HBV integrations directly contribute to HCC development through alterations of cancer driver genes, either at distance when co-localizing with copy number alterations, either locally through viral Enhancers. Together, this analysis gives new insights on HBV-associated driver mechanisms involved in hepato-carcinogenesis.

  Study EGAS00001004629

• Targeted sequencing of breast cancer susceptibility genes for 1,995 Japanese breast cancer patients

  In this study, we investigated pathogenic germline variants in 11 genes implicated in hereditary breast cancer, including BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, NBN1, in a total of 1,995 unselected Japanese women with breast cancer using targeted-capture sequencing of pooled DNA (n = 106).

  Study EGAS00001004630

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD38234__WG_

  Sequencing of LCM-derived microbiopsies from explanted lung from pulmonary fibrosis patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs.

  Study EGAS00001003324

• Genomic profiling of Follicular thyroid adenomas and carcinomas using exome-sequencing analyses

  While thyroid nodules per se are frequent (4%–50%), thyroid cancer is rare (∼5% of all thyroid nodules). The minimally invasive Fine Needle Aspiration Cytology (FNAC) is the current gold standard for the diagnosis thyroid nodule malignancy. However, proper discrimination of follicular neoplasias often require more invasive diagnostic techniques. To develop a novel molecular classification system for thyroid cancer malignancy, we performed an genomic profiling of 54 fresh frozen Follicular like thyroid samples using a whole exome sequencing approach (SureSelect V6 Target enrichment protocol and the Illumina Novaseq 6000 platform)

  Study EGAS00001005561

• Targeting AXL Kinase Uniquely Sensitizes Therapy-Insensitive Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia

  The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in leukemic stem cells. We developed a potent, selective AXL inhibitor that has excellent pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in vivo. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.

  Study EGAS00001004663

• Human breast transcriptome analysis

  Obesity is a risk factor for the development of post-menopausal breast cancer and is associated with a worse breast cancer prognosis. Here we carried out transcriptome profiling on nontumorous breast tissue to define the molecular changes that occur related to excess body fat and adipose inflammation. A second goal was to determine if blood biomarkers reflect molecular changes in the breast. Increases in a variety of pathways linked to tumor development and progression were found. Moreover, increased expression of several drug targets including aromatase, the rate-limiting enzyme for estrogen biosynthesis, and PD-1 was observed. Various blood biomarkers that are associated with either elevated risk of breast cancer or worse prognosis were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

  Study EGAS00001004665

• Res1_HT29_exp1_MC_02_03_22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Study EGAS00001006092

• Transcriptomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum

  Background; Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH.MethodsMultiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping were performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors).ResultsOverall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high ITH and were classified discordantly. Proximal tumors showed ITH related to differences in the microenvironment, while ITH within distal tumors were cancer-cell related. This subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05).ConclusionOur transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.

  Study EGAS00001004668

• To determine the genomic profiles of Triple Negative Breast Cancers (COH cohort)

  Specific BRCA and immune configurations determine optimal response to platinum-based chemotherapy in triple negative breast and ovarian carcinomas (COH_TNBC_WGS)

  Study EGAS00001006085

• Res1_H23_exp1_MC_04_03_22

  1 sample is pure plasmid DNA and 8 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Study EGAS00001006091

• Evaluation of commercial Guardant360 ctDNA test in metastatic prostate cancer

  Circulating tumor DNA (ctDNA) sequencing provides a minimally-invasive method for tumor molecular stratification. We compared the commercial Guardant360 ctDNA test to an academic sequencing approach for profiling of metastatic prostate cancer. Plasma cell-free DNA (cfDNA) from 24 patients was sequenced with a validated, prostate cancer specific targeted research panel, and sent for simultaneous Guardant360 analysis.

  Study EGAS00001003352

• Exploration of coding and non-coding variants in cancer using GenomePaint.

  GenomePaint (https://proteinpaint.stjude.org/genomepaint) is a dynamic visualization platform for whole-genome, whole-exome, transcriptome, and epigenomic data, featuring a novel design that captures the inter-relatedness between DNA variations and RNA expression. Regulatory non-coding variants can be inspected and discovered along with coding variants, and their functional impact further explored by examining 3D genome and/or ChIP-seq data generated from cancer cell lines. Further, GenomePaint correlates mutation and expression patterns with patient outcomes, and can display external data such as adult cancer datasets and user-provided custom tracks. We used GenomePaint to analyze multi-omics data from 3,652 pediatric cancers representing 16 histotypes, and demonstrate the visualization features through examples, including two that led to new insights into oncogenic mechanisms in pediatric cancer. The first is the discovery of a new class of pathogenic recurrent variants that cause aberrant splicing, disrupting the RING domain of CREBBP, a driver gene frequently mutated in relapsed pediatric leukemia. The second is the cis-activation of the MYC oncogene in a subset of B-lineage acute lymphoblastic leukemia (B-ALL) via duplication of the NOTCH1-MYC enhancer (N-ME), previously discovered only in T-lineage ALL. The regulatory impact of N-ME enhancer amplification was initially confirmed by allelic imbalance in published gene expression and ChIP-seq data and verified by additional Capture-C and fluorescence in situ hybridization data generated by follow-up experiments. These examples demonstrate the power of GenomePaint in enabling not only data visualization but also integrative genomic analysis that can lead to novel biological insight for follow-up experimental validation.

  Study EGAS00001004669

• mutational landscape of normal human breast

  The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood. Here we describe whole genome sequencing analysis of epithelial and stromal compartments from the normal breast. We aimed to study how pregnancy and age affect both the mutational burden and the clonality of the healthy breast, and the subsequent implications on breast cancer risk.

  Study EGAS00001004672

• Genomics to select patients with metastatic breast cancer for targeted therapy (microarray_oncoscan)

  Cancer progression is driven in part by genomic alterations located in oncogenes or tumor suppressor genes. The genomic characterization of cancers has shown a large interpatient heterogeneity regarding the driver alterations, leading to the concept that generating a genomic profiling by multigene sequencing in patients with cancer could allow selecting effective targeted therapies. While this concept has been broadly implemented in daily practice, there is no evidence that such approach improves patient outcome, and how to optimally select the therapy to administer. A genomic profiling using next generation sequencing and copy number analyses was performed 1462 patients with Her2-non overexpressing metastatic breast cancer included in SAFIR02 Breast trial. 238 of these patients were randomized in two trials between a targeted therapy matched to genomic alteration and a maintenance chemotherapy. The trial shows that targeted therapies matched to genomics improves progression free survival (PFS) when genomic alterations are classified level I/II according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted HR: 0.41, 90% CI: 0.27-0.61, p<0.001), but not when alterations are classified beyond level II (unadjusted HR: 1.15, 95% CI: 0.76-1.75). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with mBC.

  Study EGAS00001005586

• Molecular analysis of FIT interval colorectal cancers

  To optimize a fecal immunochemical test-based screening program, the rate of missed colorectal cancers (CRCs), so-called FIT-interval CRCs, should be minimized. A specific molecular make-up of those CRCs could be an explanation for those interval CRCs. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all precursor lesions. In this study we aimed to compare the molecular make-up of FIT-interval CRCs and screen-detected CRCs (SD-CRCs).

  Study EGAS00001004683

• Genomics to select patients with metastatic breast cancer for targeted therapy (microarray_agilent)

  Cancer progression is driven in part by genomic alterations located in oncogenes or tumor suppressor genes. The genomic characterization of cancers has shown a large interpatient heterogeneity regarding the driver alterations, leading to the concept that generating a genomic profiling by multigene sequencing in patients with cancer could allow selecting effective targeted therapies. While this concept has been broadly implemented in daily practice, there is no evidence that such approach improves patient outcome, and how to optimally select the therapy to administer. A genomic profiling using next generation sequencing and copy number analyses was performed 1462 patients with Her2-non overexpressing metastatic breast cancer included in SAFIR02 Breast trial. 238 of these patients were randomized in two trials between a targeted therapy matched to genomic alteration and a maintenance chemotherapy. The trial shows that targeted therapies matched to genomics improves progression free survival (PFS) when genomic alterations are classified level I/II according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted HR: 0.41, 90% CI: 0.27-0.61, p<0.001), but not when alterations are classified beyond level II (unadjusted HR: 1.15, 95% CI: 0.76-1.75). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with mBC.

  Study EGAS00001005587

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAEs) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127– Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

  Study EGAS00001004694

• Whole Genome sequencing of colorectal cancer patients (SG-BULK-5)

  The study was approved by the institutional review board of Singhealth (2018-2795). Ten 5-µm tissue sections were cut using standard microtomy techniques. Each collected cell population was then extracted using the allprep kit. Extracted material was then quantified using a Qubit fluorometer.

  Study EGAS00001006114

• Salivary Gland Cancer TSO500 dataset

  Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations. This research aimed to identify these actionable aberrations by NGS-based analysis of DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. DNA was extracted from archival tissue of 119 patients with various SGC subtypes and sequenced using a targeted NGS panel encompassing 523 cancer related genes (TruSight Oncology 500, TSO500). The 119 patients included 46 AdCC patients, 43 SDC patients, 15 MEC patients, 9 AciCC patients and 6 patients with other subtypes (1 secretory carcinoma, 1 polymorphic adenocarcinoma (PAC), 1 adenocarcinoma NOS, 1 myoepithelial carcinoma, 1 epithelial/myoepithelial carcinoma and 1 mixed PAC/myoepithelial carcinoma). Median exon coverage ranged from 80-904 (median 308) unique reads and the median percentage of exon coverage with at least 100 unique reads was median 96.6% in these 119 samples.

  Study EGAS00001006232