Combination of ribociclib and gemcitabine for the treatment of medulloblastoma
Group 3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3 MBs. Ribociclib CNS penetration was assessed by in vivo microdialysis and by immunohistochemistry and gene expression studies. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice orthotopically implanted with luciferase labelled mouse and human G3 MB. Pharmacokinetic-pharmacodynamic outcomes and univariable survival models were analyzed to estimate survival. Gene activity inference using NetBID and tumor differentiation analysis investigated the effects of the combination after short and long-term treatments. Tumors from mice treated with oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell cycle progression and DNA damage response, and an increase in activity and expression of genes implicated in neuronal identity and neuronal differentiation. Ribociclib is CNS-penetrant. When administered/combined with gemcitabine in orthotopic G3 MB models resulted in improved survival. Our findings, with both mouse and human patient-derived-orthotopic xenograft models, suggest that this combination therapy has promise for children with G3 MB and may represent an effective treatment strategy for other CNS malignancies.
Study
EGAS00001006001
Validation_for_human_early_embryonic_substitutions_
PCR and MiSeq validation for early embryonic substitution candidates from 400 Breast cancer patients
Study
EGAS00001001218
CRUK-ICGC Prostate Cancer Group Study
Prostate cancer somatic genomic sequencing data generated from 2011 onwards under auspices of the International Cancer Genome Consortium Prostate Cancer UK consortium (CRUK-ICGC Prostate Group), co-led by Colin Cooper and Ros Eeles, with other Principal Investigators (Brewer, Neal, Bova, McDermott, Wedge, Lynch, Massie, and Foster) and others as listed in study publications. Funded by Cancer Research UK and other funders as listed in study publications. Contents and publications related to each dataset are described with each dataset (EGAD) entry.
Our study was funded with the ambition of collecting Whole Genome DNA sequence data from 250 prostate cancers, with matching transcriptome and methylome data.
The original aims of the project were:
1.To understand the significance of multifocal prostate cancer.
2.To understand the clinical heterogeneity of prostate cancer to devise markers for predicting outcome and for drug targeting.
3.To understand the molecular basis of development and spread of castration-resistant and metastatic disease
4.To understand the aetiology of prostate cancer particularly the large variation in incidences that occur in different populations and ethnic groups.
Please see https://doi.org/10.5281/zenodo.4022439 for links between sample IDs reported in literature and EGA IDs.
Study
EGAS00001000262
BCAC TIIC Data
Data on spatially-resolved tissue infiltrating immune cells (TIICs) from 17,265 breast cancer patients of European descent, from studies participating in the Breast Cancer Association Consortium, together with linked clinical data.
Study
EGAS50000001477
Organoid_Derivation_Project__WGS
Generation of normal and cancer organoids for sequencing as part of the WTSI-CRUK international collaboration with NCI (in HCMI) to generate the next generation of cancer cell lines
Study
EGAS00001002222
RNAseq data to study PRPF6 regulated splice forms in colon cancer cell lines
Alternative splicing plays critical roles in differentiation, development, and cancer (Pettigrew et al., 2008; Chen and Manley, 2009). The recent identification of specific spliceosome inhibitors has generated interest in the therapeutic potential of targeting this cellular process (van Alphen et al., 2009). Using an integrated genomic approach, we have identified PRPF6, an RNA binding component of the pre-mRNA spliceosome, as an essential driver of oncogenesis in colon cancer. Importantly, PRPF6 is both amplified and overexpressed in colon cancer, and only colon cancer cells with high PRPF6 levels are sensitive to its loss. Our data clearly point to an important role for PRPF6 in colon cancer growth and suggest that a better understanding of its role in alternative splicing in colon cancer is warranted. To determine the specific alternative splice forms that PRPF6 regulates in colon cancer, we plan three experiments: 1. The first involves knocking down expression of PRPF6 in two different cancer cell lines with 3 different siRNAs, and then completing RNA-seq to determine the gene expression changes that occur relative to a non-targeting control siRNA. Because of the role for PRPF6 in pre-mRNA splicing, we especially want to quantify the changes in splice-specific forms of all genes genome-wide to identify genes whose splicing is altered upon PRPF6 knockdown. 2. The second involves immunoprecipitating PRPF6 from two different cancer cell lines and isolating any RNA that is bound to PRPF6, since PRPF6 is an RNA-binding protein. We then want to carry out RNA-seq to identify which RNA molecules co-immunoprecipitated with PRPF6. This will help us determine possible functions for PRPF6 in regulating colon cancer growth. 3. The third involves overexpressing PRPF6 in cell lines and then carrying out RNA-seq to identify any changes in splice-specific gene expression. This will allow us to determine whether increased PRPF6 expression is sufficient to drive alternative splicing changes.
Study
EGAS00001000761
Colorectal_organoids_and_tumour_tissue___Whole_Genome_X10
Whole genome sequencing of single cell derived organoids from normal colon tissue and colorectal cancer.
Study
EGAS00001001100
Whole Genome Sequence and RNASeq Samples for Lung Cancer
Short Read Whole Genome Sequence and RNASeq Samples for Lung Cancer
Study
EGAS00001007832
Mutant p53 confers gain-of-function transcriptional activity in liver cancer
Mutant p53 confers gain-of-function transcriptional activity in liver cancer
Study
EGAS00001005779
COMPASS Next Generation Sequencing WGS data
Whole genome sequencing data for Pancreatic Cancer Samples from the COMPASS clinical trial
Study
EGAS50000001091
RESOLVE_trial_targeted_sequencing_data
RESOLVE: Abemaciclib + Letrozole +/_- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer
Study
EGAS50000001202
Breast cancer DNA repair
Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double strand break (DSB) repair and high sensitivity to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In the present study we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancers (BrC) tissue: the RECAP test.Methods Fresh samples of 170 primary BrC were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor infiltrating lymphocytes (TILs) and microsatellite instability (MSI).Results RECAP was completed successfully in 148 out of 170 samples (87%). 24 tumors showed HRD (16%), while 6 tumors were HR intermediate (HRi) (4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases. Several non-BRCA deficient HRD tumors showed BRCAness mutational signatures, suggesting that they are also bona fide HRD cases. HRD tumors showed an increased incidence of high TIL counts (p=0.023) compared to HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in BrC (1%) (p=0.017).Conclusion The RECAP test is a robust assay detecting both BRCA1/2 deficient and BRCA1/2 proficient HRD tumors, suggesting that this test identifies approximately 50% more patients that may benefit from PARPi treatment than BRCA gene testing only.
Study
EGAS00001002792
RNA-seq data from Non Small Cell Lung Cancer (NSCLC) samples
RNA-seq data from Non Small Cell Lung Cancer (NSCLC) samples
Study
EGAS00001004032
Palbociclib resistance analyses on breast cancer bone metastasis PDX
Identify mecanisms of metastatic breast cancer resistance to palbociclib by RNAseq analyses.
Study
EGAS00001006428
BRAF_and_MEK_resistant_cell_line_clones
The Sanger Institute has the largest collection of genetically-characterised cancer cell lines world-wide (we have collected >1000 human cancer cell lines which are being screened against >400 cancer therapeutics (http://www.sanger.ac.uk/genetics/CGP/translation). These lines have been characterized to the level of gene copy number, gene expression and cancer gene mutation sequence data. This has enabled us to select melanoma lines with varying BRAF mutational status and that show sensitivity to a range of BRAF inhibitors. Sensitive lines are being used to generate resistant clones by serial exposure to increasing concentrations of BRAF and MEK inhibitors and these are being characterised by genome-wide copy number analysis as well as by whole exome sequencing.
Study
EGAS00001000172
Whole genome analysis of mutation hotspots in gastric cancer
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. In this study, we unbiasedly analysed 212 gastric cancer whole genomes to identify recurrently mutated non-coding regions in gastric cancer. Applying comprehensive statistical approa- ches to accurately model background mutational processes, we observe significant enrich- ment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs).
Study
EGAS00001002872
Repertoire and clinical hierarchy of AR locus alterations in castration-resistant prostate cancer
Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiology remain incompletely understood. Here, we analyzed 3399 plasma cell-free DNA samples and 1988 leukocyte DNA samples from 1995 metastatic prostate cancer patients with matched clinical data and extensive AR locus coverage.
Study
EGAS50000001101
INSIGHT: VHL Case Report
The overall goal of this study is to uncover contributors to inherited cancer through analysis of individuals and families with, or at risk of, a hereditary cancer syndrome. In addition, we hope to elucidate novel mechanisms of tumourigenesis in hereditary cancer patients. This specific report highlights a rare case of VHL mosaicism and shows the value of tissue testing in VHL variant negative cases.
Study
EGAS00001005895
Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer. Higher mutation rates (MR) in metastatic tumours
Building on the observation that MR appears to be a unique and inheritable feature of each cancer cell, we explored whether MR is subject to selective pressure during cancer progression. These data suggest that a higher MR is selected during CRC metastatic progression.
Study
EGAS50000000147
Comprehensive genomic characterization of early stage bladder cancer - Total RNA-seq data
This study looks at the non muscle invasive bladder cancer subtypes based on totRNAseq data of 414 bladder cancer samples collected in different European centers within the UROMOL project. All samples were sequenced using paired reads on Illumina platforms. The reads are mapped to hg38.
Study
EGAS50000000512
Assessment of genomic copy number alterations in breast cancer
The aim of this study was to assess genomic copy number alterations in a panel of breast cancer cell lines. These data were used to identify common aberrations associated with breast cancer, and also to identify aberrations associated with response to therapeutic compounds.
Study
EGAS00001000585
Korean Lung Cancer - 36 pair WES data
This study includes 36 paired samples of Korean Lung Cancer paitients.36 Lung Cnacer samples are paired with each normal(Saliva derived for control) sequencing data.The results of this WES study were analyzed by Mutect and GATK for ranking germline variants and cancer variants to make mutational profile matrix.
Study
EGAS00001002843
RRBS data from TRACERx non-small cell lung cancer (NSCLC) tumours and matched normal adjacent tissue.
TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC).
Study
EGAS00001008071
Colorectal cancer functional annotation - ChIP
ChIP-seq data for multiple colorectal cancer cell lines (H3K4me1, H3K4me3, H3K27ac, H3K27me3, H3K36me3, CTCF)
Study
EGAS50000000207
Organoid_Derivation_Project__TGS
Sequencing of tissue samples and their derived organoids from oesophageal, pancreatic and colorectal cancer patients.
Study
EGAS00001002221
