3885 results for "*geneti*"

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• GILD_ExomeSeq_PTNHL

  This study is meant to gain further knowledge in haematological cancers. Patients samples (mainly DNAs or PCR products) from haematolocical cancer patients will be sequenced, and the outputs will be correlated to their diagnosis and/or prognosis; the findings may also add more insight into the understanding of biology in this type of tumour. We will be sequencing Primary Testicular Lymphomas (PTL) to identify genetic drivers of this rare cancer

  Study EGAS00001001613

• Genome-wide genetic and epigenetic dataset of pancreatic acinar cell carcinomas

  Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. To identify potential targets for personalized treatment, integrative genome- and epigenome-wide analyses were performed. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are known. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies potential novel therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

  Study EGAS00001002533

• Genomic landscape of human diversity across Madagascar

  Although situated ~400 km from the east coast of Africa, Madagascar exhibits cultural, linguistic, and genetic traits from both Southeast Asia and Eastern Africa. The settlement history remains contentious; we therefore used a grid-based approach to sample at high-resolution the genomic diversity (including maternal lineages, paternal lineages, and genome-wide data) across 257 villages and 2704 Malagasy individuals. We find a common Bantu and Austronesian descent for all Malagasy individuals with a limited paternal contribution from Europe and the Middle East. Admixture and demographic growth happened recently, suggesting a rapid settlement of Madagascar during the last millennium. However, the distribution of African and Asian ancestry across the island reveals that the admixture was sex biased and happened heterogeneously across Madagascar, suggesting independent colonization of Madagascar from Africa and Asia rather than settlement by an already-admixed population. In addition, there are geographic influences on the present genomic diversity, independent of the admixture, showing that a few centuries is sufficient to produce detectable genetic structure in human populations.

  Study EGAS00001002549

• MED12L Gene Alterations Define Aggressive BRCA2-Mutant Prostate Cancers

  Germline mutation of BRCA2 increases the lifetime risk of developing prostate cancer (PCa) by over 700%. BRCA2-mutant PCa have poorer prognosis than sporadic PCa, with rapid development of metastatic, castrate-resistant prostate cancer (mCRPC) and 5-year cancer-specific survival rates of ~50-60%1-4. Despite this, unique genomic driver events that explain the aggressiveness of localized BRCA2-mutant PCa are lacking. We used whole-genome sequencing to fully characterize 14 BRCA2-mutant PCa and demonstrate that BRCA2-mutant PCa is associated with increased genetic instability and a mutually exclusive mutational burden when compared to sporadic PCa. Importantly, BRCA2-mutated cancers are defined by unique copy number gains and hypomethylation events, including alterations in the MED12L/MED12 axis, which are found solely in mCRPC and are enriched in PCa tumours harbouring aggressive intraductal carcinoma (IDC-P) pathologic sub-types. Our findings begin to explain the clinical entity of BRCA2-mutated PCa as these tumours have a unique and aggressive genotype de novo, associated with IDC-P and mCRPC, even in the hormone-naive setting.

  Study EGAS00001001615

• Inhibiton of the GABPB1L-containing GABP tetramer is sufficient to reverse replicative immortality in TERT promoter mutant glioblastoma cells.

  Over 50 types of cancer acquire TERT promoter mutations. These single point mutations reactivate telomerase, allowing for indefinite maintenance of telomere length and enabling cellular immortalization. The transcription factor binding site created by the point mutations specifically recruit the ETS factor GABP, a multimeric transcription factor composed of the GABPα and GABPβ subunits. GABP can form two functionally independent transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that genetic disruption of GABPβ1L, a tetramer forming isoform of GABPβ that is dispensable in normal development, results in TERT silencing in a TERT promoter mutation dependent manner. Failure to activate TERT expression by GABPβ1L culminates in telomere dysfunction, DNA damage, and mitotic cell death exclusively in TERT promoter mutant cells. Furthermore, exogenous expression of TERT is sufficient to prevent telomere degradation and loss of cell viability in GABPβ1L-reduced lines bearing the mutant TERT promoter. Orthotopic injection of tetramer-deficient mutant TERT promoter GBM cells rendered lower tumor burden and prolonged the overall survival of the tumor-bearing mice. These results highlight the potentially widespread role of GABPB1L in enabling replicative immortality of TERT promoter cancers.

  Study EGAS00001002582

• Whole_genome_sequencing_of_Italian_genetic_isolates__Friuli_Venezia_Giulia

  Low coverage whole genome sequencing of samples from individuals from Friuli Venezia Giulia, an Italian genetic isolate population.

  Study EGAS00001000252

• Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

  Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

  Study EGAS00001002606

• Whole Genomes Define Concordance in Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer

  Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common solid epithelial tumour. Multiple failed clinical trials necessitate newer approaches to understand the molecular etiology of this disease. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) may serve as pre-clinical disease models; however, characterization remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of tumours and matched PDX and PDO from patients with PDAC. Our data show that PDX and PDO recapitulate PDAC tumourigenesis with respect to simple somatic mutations and copy number changes, and capture major structural variation events.

  Study EGAS00001002597

• Chracterising_cellur_pathways_underlying_CD3_CD28_activation_of_human_CD4__cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Isolated memory and naïve T cells were activated using anti-CD3, anti-CD28 or both in combination. As a control we cultured cells in the same conditions but without the stimuli. We carried Chipmentation using the H3K27ac antibody on 200,000 cross-linked cells. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002599

• Whole-exome sequencing of breast cancer metastasis and corresponding blood samples

  This study included samples from metastatic breast cancer patients who underwent a biopsy in the context of SAFIR01 (NCT01414933), SAFIR02 (NCT02299999), SHIVA (NCT01771458) and MOSCATO (NCT01566019) prospective trials. These French multicentre trials used high throughput genome analysis on fresh frozen tumor biopsies as a therapeutic decision tool for metastatic cancer patients, with solid cancers (SHIVA, MOSCATO) or specifically with breast cancer (SAFIR01, SAFIR02). All patients gave their informed consent for translational research and genetic analyses of their somatic DNA. Overall, whole-exome sequencing for a total of 216 pairs of metastatic tumor and unmutated DNA derived from corresponding blood samples was performed using Illumina technology. The results of the analysis of the mutational profile of metastatic breast cancer was reported in Lefebvre et al. (PMID:28027327).

  Study EGAS00001001695