5032 results for "*oma"

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• Barcelona_kids_with_melanoma

  This set of samples is composed of eight young people (7-16 years old) that have developed melanoma with first-degree relatives that have also developed cancer, which suggests a genetic component to their disease. Here we want to sequence these samples in order to find the causative mutations. As these samples do not carry any of the high-penetrance mutations known to date, finding the genes(s) responsible will offer new insights into the genetic mechanisms underlying predisposition to melanoma.

  Study EGAS00001000733

• Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

  RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II1, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC42,3. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

  Study EGAS00001001916

• 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

• Germline variants in patients diagnosed with both uveal and cutaneous melanoma

  We sequenced the constitutional DNA from patients affected by both uveal and cutaneous melanoma.

  Study EGAS00001007584

• Targeting the DNA Repair Pathway in Ewing Sarcoma

  Ewing’s Sarcoma is a bone and soft tissue tumor that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive but survival for metastatic and recurrent disease is poor. Whole genome sequencing of 19 Ewing’s Sarcoma tumors showed that STAG2 was mutated in 10% (2/19) of the tumors and STAG2 protein was absent in 14% (13/106) tumors by immunohistochemical staining. Previous studies have shown that glioblastoma cells lacking STAG2 are more sensitive to poly-ADP ribose polymerase (PARP) inhibitors. We found that Ewing’s Sarcoma cell lines are sensitive to PARP inhibitors irrespective of STAG2 protein expression. Ewing Sarcoma cell lines are defective in double strand DNA break repair. PARP inhibitor cytotoxicity in Ewing’s Sarcoma cells was potentiated 10-1,000 fold by DNA damaging agents (irinotecan and temozolomide). To extend these studies in vivo, we developed an orthotopic Ewing’s Sarcoma mouse model and performed pharmacokinetic and pharmacodynamic studies with three different PARP inhibitors (BMN-673, olaparib and veliparib) in clinical development for pediatric cancer. Those data were used to design preclinical phase I studies to identify tolerable drug combinations for pilot efficacy testing (preclinical phase II). Based on the results of the preclinical phase I/II data, we performed a double blind, randomized, placebo controlled preclinical phase III trial with 274 mice in 15 treatment groups. Irinotecan administered in a low-dose protracted schedule optimized for pediatric patients was an effective DNA damaging agent to combine with olaparib and BMN-673 and was better tolerated than combinations with temozolomide. Combining olaparib or BMN-673 with irinotecan and temozolomide gave complete and durable responses in over 80% of the mice.

  Study EGAS00001000839

• Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma

  Smoothened inhibitors are currently being investigated for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). The majority of BCC patients treated with vismodegib experience significant clinical benefit, however, a small number of patients develop resistance. Knowledge of resistance mechanisms can generate predictive biomarkers and is critical for the design of additional therapeutic strategies aimed at circumventing resistance. To investigate mechanisms of resistance to vismodegib in BCC we sequenced and profiled biopsies from patients who initially responded to treatment and subsequently progressed on drug.We find that resistance is associated with re-activation of the Hedgehog (Hh) pathway through diverse mechanisms, including concurrent copy number alterations in the downstream Hh pathway components SUFU and GLI2, as well as novel SMO mutations that reduce sensitivity to vismodegib. The latter fall into two classes: those that activate SMO and those that directly affect the vismodegib-binding pocket. Additionally, we observe evidence of clonal selection of SMO mutations and intra-tumor heterogeneity of resistance mechanisms, which implies diverse and combinatorial strategies are required to overcome resistance.

  Study EGAS00001000845

• Integrative_Oncogenomics_of_Multiple_Myeloma

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from Multiple Myeloma patient DNA and matched normal DNA from the same patients. Two lanes of Illumina GA sequencing will be performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000036

• The Genomic Landscape of Childhood and Adolescent Melanoma

  Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CM), 3 melanomas arising in congenital nevi (CNM), and 5 spitzoid melanomas (SM), using various platforms, including whole genome or exome sequencing, molecular inversion probe assay, and/or targeted sequencing. CM demonstrated a high burden of somatic single nucleotide variations (SNV), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNV consistent with UV damage. By contrast, the 3 CNM contained an activating NRAS Q61 mutation and no TERT-p mutations. SM were characterized by chromosomal rearrangements resulting in activated kinase signaling in 40%, and an absence of TERT-p mutations except for the one SM that succumbed to hematogenous metastasis. We conclude that pediatric CM has a very similar UV-induced mutational spectrum to that found in the adult counterpart, emphasizing the need to promote sun protection practices in early life and to improve access to therapeutic agents being explored in adults in young patients. By contrast, the pathogenesis of CNM appears to be distinct. TERT-p mutations may identify the rare subset of spitzoid melanocytic lesions prone to disseminate.

  Study EGAS00001000901

• Reconstruction of complex rearrangement patterns causing the initiation of clear cell renal cell carcinoma.

  The genomic hallmark of clear cell renal cell carcinoma is the loss of the short arm of chromosome three. This appears to be the earliest genomic event in the formation of these cancers. Often chromosome 3 is lost at the same time as part of chromosome 5 is duplicated via an unbalanced translocation, often with features consistent with focal chromothripsis. In this study, we sought to reconstruct the chromothriptic event that underlies the initiation of kidney cancer. We used long read sequencing (promethION, Oxford Nanopore Technologies) of patient tumour-derived DNA to elucidate how a single cell division error can generate cancer genome complexity.

  Study EGAS00001004015

• Molecular Attributes Underlying Central Nervous System and Systemic Relapse in Diffuse Large B-cell Lymphoma

  Central nervous system (CNS) relapse in diffuse large B-cell lymphoma remains a significant conundrum. While clinical risk scores and biomarkers allow the identification of patients with higher risk of CNS relapse, their predictive ability is low. Herein, we report findings from a comprehensive study examining gene expression changes, mutations and clonal evolution. Firstly, considering diagnostic samples from patients with CNS relapse, systemic relapse or no relapse, we found a striking enrichment of gene expression changes reflecting protein biosynthesis in patients who experienced CNS or systemic relapse. Furthermore, diagnostic specimens of relapsing cases were characterized by low immune infiltrates. The most discriminative gene feature in our analysis was SLAMF1, high expression of which was associated with favourable outcomes. Next, we assessed whether specific gene mutations were associated with subsequent CNS or systemic relapse. Activated B-cell-like genes such as PIM1, CD79B and PRDM1 were more frequently mutated in cases with CNS relapse, whereas TP53, BCL2 and FOXO1 mutations were associated with systemic relapse. Lastly, we performed tumor evolution analysis in five patients, identifying significant clonal divergence that accompanied CNS relapse. In summary, we identified both common biology underlying both CNS and systemic relapse, independent of cell-of-origin (COO), and specific COO-enriched gene mutations that conferred a higher risk of either CNS or systemic relapse. Moreover, we identified a pattern of clonal evolution that can explain difficulties in both predicting and treating CNS relapse.

  Study EGAS00001004057