8224 results for "canc*"

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• Exploration of CNV’s and SNV’s in cancers with well-known genetic rearrangements: Identification of additional genetic changes in rearrangements-driven cancer

  Specific cancers are well known to have specific gene rearrangements. Representative cancer is chronic myeloid leukemia (CML) which is famous for BCR/ABL gene rearrangements. By the way, also genetic rearrangements are not infrequently found in acute leukemia, and those include CBFB/MYH11 rearrangements, PML/RARA rearrangements, AML/ETO rearrangements, and BCR/ABL rearrangements. The situation is same is for lung adenocarcinoma of non-smokers and prostate cancers, and ALK and RET gene rearrangements are recently found. However, not all these rearrangements are sufficient to develop cancer, and it is suggested that some genetic aberrations are required for the development and progression of cancer in addition to these genetic rearrangements. In this study, we have a plan to explore the existence of additional genetic changes including single nucleotide variants (SNV’s) and copy number variations (CNV’s) in cancers with specific genetic rearrangements so as to define additional genetic changes that confer full oncogenic potential to cancer cells. So as to look at SNV’s and small indels, we are going to use whole exome sequencing (WES) data. And as for CNV’s, we are going to use array-CGH data. Also, to check the functionality of these genetic changes, we are going to use whole transcriptome data (WTS). In addition, in samples with whole genome sequencing (WGS ) data, we are going to explore genetic changes in intronic regions also. In fact, we sequenced 10 AML samples which are known to have specific genetic rearrangements. Analysis of these WGS, WES and WTS data are under the way. If we have a chance to access WES, array-CGH and WTS data of other cancer samples with specific genetic rearrangements, we would be able to compare additional genetic changes required for oncogenesis in cancer cells with various genetic rearrangements. We hope this result will enlighten our understanding of cancer genetics further.

  Study EGAS00001000673

• Study of pediatric hepatocellular carcinoma caused by bile salt export pump deficiency

  Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. We mapped the acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause the onset of chronic inflammation that develops into cancer. In both human and mouse cancer genomes we found few somatic point mutations with no impairment of cancer genes, but instead massive gene amplification and rearrangements. This genomic landscape differs greatly from that of virus- and alcohol-associated liver cancer. Copy number gains preferentially occurred at late stages of cancer development and frequently targeted the MAPK signaling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retarded cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be clearly distinguished from those determined by other etiological factors.

  Study EGAS00001000749

• Targeted_gene_screen_of_drug_resistant_organoids

  Sequencing of drug resistant organoids

  Study EGAS00001001797

• The KATHERINE study of adjuvant trastuzumab emtansine in HER2-positive breast cancer: analysis of patients with HER2-negative residual invasive disease on re-testing

  Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the core biopsy with HER2-negative central testing on their corresponding surgical specimen. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.

  Study EGAS00001006037

• SeqControl: Process Control for DNA Sequencing

  As next-generation sequencing (NGS) continues to increase in speed and throughput, routine clinical and industrial application draws steadily closer. These “production” uses of NGS will require enhanced quality-monitoring and quality-control to optimize output and reduce costs. We therefore developed a framework called SeqControl for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, base-wise coverage and base-wise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references we derive multivariate models that predict sequencing quality and depth. SeqControl robustly predicts how much sequencing is required to reach a given coverage depth (AUC = 0.993), accurately classifies clinically relevant formalin-fixed paraffin-embedded samples and makes predictions from as little as 1/8 of a lane of sequencing data (AUC = 0.967). These techniques can be immediately incorporated into existing NGS pipelines to monitor data quality in real-time. SeqControl represents a first step towards statistical process-control for NGS.

  Study EGAS00001000899

• The_Causes_of_Clonal_Blood_Cell_Disorders_Study___SCOR_Custom

  We took a bone marrow aspirate and peripheral blood samples from a healthy patient aged around 60, and use flow cytometry to isolate 100 HSCs, 50 MEPs, and 50 GMPs. We grew these up into colonies, then whole genome sequenced each colony. Somatic mutations act as a unique barcode for each clone. We have designed a panel for targeted resequencing of the mutations that we find. We are now looking for these mutations in the peripheral blood, to see the dynamics of how HSCs contribute to the peripheral blood in health.

  Study EGAS00001002257

• Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

  Untreated prostate cancers rely on androgen receptor (AR) signaling for growth and survival, forming the basis for the initial efficacy of androgen deprivation therapy (ADT). Yet, the disease can relapse and progress to a lethal stage termed castration-resistant prostate cancer (CRPC). Reactivation of AR signaling represents the most common driver of CRPC growth and next generation AR signaling inhibitors (ARSIs) are now used in combination with ADT as a first line therapy. However, ARSIs can result in selective pressure generating AR-independent tumors. The transition from AR-dependence frequently accompanies a change in phenotype resembling developmental trans-differentiation or ‘lineage plasticity’. Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity. However, most AR-null tumors do not exhibit neuroendocrine features and are classified as ‘double-negative prostate cancer’, the drivers of which are poorly defined. Lineage plasticity studies in CRPC are limited by the lack of genetically defined patient-derived models that recapitulate the disease spectrum. To address this, we developed a biobank of organoids generated from patient biopsies to study the landscape of metastatic CRPC and allow for functional validation assays. Proteins called transcription factors (TFs) are drivers of tumor lineage plasticity. To identify the key TFs that drive the growth of AR-independent tumors, we integrated epigenetic and transcriptomic data generated from CRPC models. By presenting a map of the chromatin accessibility and transcriptomic landscape of CRPC using a diverse biobank of organoids, PDXs and cell lines that recapitulate the heterogeneity of metastatic prostate cancer, we validate CRPC-AR and CRPC-NE subtypes and reveal two subtypes of AR-negative/low samples as well as their respective masterTFs. Additional analysis revealed a model in which YAP, TAZ, TEAD and AP-1 function together and drive oncogenic growth in CRPC-SCL samples. Overall, we show here how an approach to stratify CRPC patients into four subtypes using their transcriptomic signatures can potentially inform upon appropriate clinical decisions.

  Study EGAS00001006059

• Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

  Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

  Study EGAS00001000055

• Whole_genome_sequencing_of_rhabdomyosarcoma_tumouroids

  The aim of this study is to investigate the genomic landscape of human cancer.

  Study EGAS00001008270

• High Grade Serous Ovarian Carcinomas Originate in the Fallopian Tube

  High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. To provide insights into the origins of HGSOC, we We performed whole-exome sequence and copy number analyses of laser-capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients with HGSOC. The majority of tumor-specific sequence and structural alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN genes. An eEvolutionary analyseis revealed that p53 signatures and STICs were are the precursors of ovarian carcinoma which in turn gave rise to metastatic lesionsand identify a. In one patient we identified a second STIC as a metastasis in the fallopian tube opposite from the affected ovary. These analyses revealed a window of seven years between the development of a STIC and the initiation of ovarian carcinomas, with development of metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for the prevention, early detection and therapeutic intervention of this disease.

  Study EGAS00001002589