3798 results for "*oma"

in 35.22 milliseconds.

• Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

  Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, aflatoxin B1 and HBV infection. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV) and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 24% of the tumors, we identified genetic alterations potentially targetable by FDA-approved drugs. In conclusion, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.

  Study EGAS00001001002

• Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

  Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3'UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NFκB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

  Study EGAS00001002936

• Adeno-associated virus in the liver: natural history and consequences in tumor development

  Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (40-80%). AAV infection has long been considered as non-pathogenic1, however few years ago we reported for the first time recurrent clonal AAV2 insertion in the pathogenesis of human hepatocellular carcinoma (HCC) developed on normal liver. These clonal viral insertions target cancer driver genes, including CCNA2, CCNE1, TERT, TNFSF10 and MLL4, leading to their overexpression. The viral inserted sequences involved in almost all the cases the 3’ inverse tandem repeat (ITR) of AAV2, which is important for virus integration in host DNA and exhibits a promoter/enhancer activity. Here, we used RNA sequencing (RNA-seq) to investigate their functional impact on the tissue, such as fusion transcript generation events.

  Study EGAS00001003310

• 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

• Enhanced detection of circulating tumor DNA by fragment size analysis

  Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on sensitivity for detecting genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for non-invasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 cancer patients using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90–150 bp, and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90–150 bp improved detection of tumor DNA, with more than 2-fold median enrichment in >95% of cases, and more than 4-fold enrichment in > 10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with AUC> 0.99 compared to AUC < 0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91, compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection. This could reduce the required depth of cfDNA sequencing for clinical applications, earlier diagnosis and study of tumor biology.

  Study EGAS00001003258

• Summary statistics from genome-wide association study in glioma of 12,488 cases and 18,169 controls.

  Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,488 cases and 18,169 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  Study EGAS00001003372

• Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

  FOXO1 has an oncogenic role in adult germinal center derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1 resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3 or members of the phosphatidylinositol 3’ OH kinase (PI3K) signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

  Study EGAS00001003719

• Genomic and epigenomic insights into the origin, pathogenesis and clinical behavior of mantle cell lymphoma subtypes

  Mantle Cell Lymphoma can be subdivided into conventional (cMCL) and leukemic non-nodal MCL (nnMCL), which differ in the cell of origin, gene expression, biological characteristics and clinical evolution. Using genomic, epigenomic and transcriptomic data we identified common and particular alterations in the two subtypes, either point mutations, copy number alterations or structural variants some of them with prognostic impact.

  Study EGAS00001004165

• OpACIN-neo – A Multicenter Phase 2 Study to identify the Optimal neo-Adjuvant Combination scheme of Ipilimumab and Nivolumab – Whole exome sequencing

  The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo study (NCT02977052) to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. 86 patients with macroscopic stage III melanoma were randomised to one of three dosing schedules: arm A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks; arm B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks; or arm C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3mg/kg once every 2 weeks. Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. Pathological responses occurred in 24 (80%) patients in group A, 23 (77%) in group B, and 17 (65%) in group C. The 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (p<0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pathologic response rate (pRR) was 100% in patients with high IFN-γ score/high TMB, patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score.

  Study EGAS00001004832

• Targeted sequencing of follicular lymphoma tumour samples from the UK's Haematological Malignancy Research Network

  Follicular lymphoma displays morphological and clinical heterogeneity, underpinned by shared molecular pathogenesis. Mutations in epigenetic regulators alongside t(14;18) have been identified as disease initiating events. Additional mutational diversity suggests disease heterogeneity. Whether this resolves into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n=548) diagnosed in a catchment population of ~4 million (14 centers), with full clinical follow-up (n=538) that included 96 DLBCL transformations. We investigated whether molecular subclusters of FL can be identified, and whether mutational data provide predictive information relating to transformation.

  Study EGAS00001005238