5495 results for "*oma"

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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

• WGS of liver cancer in the Japanese population

  Hepatocellular carcinoma (HCC) is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide, with an estimate of more than 700,000 new cases each year. The most established risk factors of HCC are chronic HBV and HCV infection. HBV infection is responsible for over 50% of the worldwide attributable risk of HCC, especially in East Asia and Africa, while in Japan and several Western countries HCV infection is the most common risk factor for HCC. To gain insights into the molecular alterations of virus-associated HCC, we performed whole genome sequencing (WGS) of 321 HCC tumors from 159 patients. This work was performed as a part of the ICGC (International Cancer Genome Consortium) project.

  Study EGAS00001000678

• Integrative genomic profiling of hepatocellular adenomas reveals recurrent FRK activating mutations and mutational processes of malignant transformation

  Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraception. Here, exome sequencing identified novel recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation and cell proliferation sensitive to Src inhibitors. We also found new recurrent mutations activating JAK1, gp130 or ß-catenin. Chromosome copy-number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCA transformed to hepatocellular carcinoma revealed ß-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, new therapeutic targets and the key genomic determinants of the adenoma-carcinoma transformation sequence. Significance: Malignant transformation of benign adenoma into malignant carcinoma is frequently observed in several epithelial tumor types. Adenoma-carcinoma transition is crucial for the patient prognosis, however, little is known on the molecular mechanisms involved. Here, we performed an integrated genomic analysis of hepatocellular adenomas (HCA). Among several novel gene mutations, we identified recurrent somatic mutation activating FRK, a Src-like kinase. FRK activating mutations induce STAT3 activation and cell proliferation that can be targeted by Src inhibitors. Focusing on malignant transformation of HCA in hepatocellular carcinoma, we identified CTNNB1 and TERT promoter mutation as early and late genomic events involved in adenoma-carcinoma transition. In conclusion, we propose new therapeutic targets and an identification of adenomas with the highest risk of malignant transformation. Highlights: - FRK is activated by somatic recurrent mutations. - FRK mutants promote cell proliferation sensitive to src inhibitors. - CTNNB1 activation is an early event in HCA transformation. - TERT promoter mutations are associated with adenoma-carcinoma transition.

  Study EGAS00001000679

• Recurrent epimutations activate gene body promoters in primary glioblastoma

  Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein.

  Study EGAS00001000685

• Whole-Genome sequencing of hepatocellular carcinomas

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome and whole exome sequencing together with CGH-SNP, methylome and transcriptomic profiling. For this purpose, a series of 500 liver tumors are collected through the French National Liver Collection and these samples will be analyzed using the different omics technologies. The data will be deposited in the ICGC and EGA database to be publically available for the scientific community. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before. The dataset will include 50 whole genome sequencing tumor/germline pairs, of which 6 are deposited in February 2014.

  Study EGAS00001000706

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

  Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT patients in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors, but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

  Study EGAS00001000714

• Germline and somatic SMARCA4 mutations characterize small-cell carcinoma of the ovary, hypercalcemic type.

  Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years1. We sequenced the exomes of six individuals from three SCCOHT families. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth family, which also possessed a segregating SMARCA4 germline mutation. All familial tumors sequenced harboured either a somatic mutation or loss of the wild-type allele. Immunohistochemical (IHC) analysis of these and additional familial and non-familial cases showed loss of the SMARCA4 protein (BRG1) in 38/40 tumors overall. Sequencing of cases with available DNA revealed at least one germline or somatic deleterious SMARCA4 mutation in 30/32 cases. Additionally, the SCCOHT cell line BIN-67 contained bi-allelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to genetic counseling and new treatment approaches.

  Study EGAS00001000721

• UQCCR/QCMG brain metastasis sequence analysis

  The present study, conducted by the UQCCR and QCMG at the University of Queensland, investigated the genomic landscape of brain metastases from 36 patients (with matched normal samples) that originated from a range of primary tumour sites (including breast (11), lung (18), melanoma (6) and oesophageal (1)) utilizing Illumina 2500 HiSeq Exome sequencing. Somatic substitutions were identified using a dual qSNP/GATK calling strategy. The Pindel tool was used to determined short insertions and deletions. Key biological pathways were investigated using pathway analysis tools. It is envisaged that the current work may provide important biological insights into the genomic characterization and evolution of brain metastasis and additionally identify druggable targets of clinical relevance.

  Study EGAS00001000722

• ICGC Oesophageal adenocarcinoma - normal samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data. - This study contains the Normal tissue samples.

  Study EGAS00001000723

• ICGC Oesophageal adenocarcinoma - 100 tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000724

• ICGC Oesophageal adenocarcinoma - tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000725

• ICGC Oesophageal adenocarcinoma - Barrett's samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000726

• Chordoma_Extension_Study

  Extension analysis to pursue candidate genes of interest in chordoma

  Study EGAS00001000892

• ICGC Oesophageal adenocarcinoma - lymph-node samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000727

• Whole Exome Sequencing of cohorts of Mutant Braf mouse model melanoma DNA and germline DNA.

  Whole Exome Sequencing of cohorts of Mutant Braf mouse model melanoma DNA and germline DNA. The cohorts are (1) Mutant Braf mouse model melanomas, (2) Mutant Braf mouse model melanomas from UVR exposed mice and (3) Mutant Braf mouse model melanomas from UVR exposed, sunscreen protected mice.

  Study EGAS00001000729

• 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

• Next-Generation Sequencing of RNA and DNA Isolated from Paired Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Samples of Human Cancer and Normal Tissue

  Formalin-fixed, paraffin-embedded (FFPE) tissues are an invaluable resource for clinical research. However, nucleic acids extracted from FFPE tissues are fragmented and chemically modified making them challenging to use in molecular studies. We analysed 23 fresh-frozen (FF), 35 FFPE and 38 paired FF/FFPE specimens, representing six different human tissue types (bladder, prostate and colon carcinoma; liver and colon normal tissue; reactive tonsil) in order to examine the potential use of FFPE samples in next-generation sequencing (NGS) based retrospective and prospective clinical studies. Two methods for DNA and three methods for RNA extraction from FFPE tissues were compared and were found to affect nucleic acid quantity and quality. DNA and RNA from selected FFPE and paired FF/FFPE specimens were used for exome and transcriptome analysis. Preparations of DNA Exome-Seq libraries was more challenging (29.5 % success) than that of RNA-Seq libraries, presumably because of modifications to FFPE tissue-derived DNA. Libraries could still be prepared from RNA isolated from two-decade old FFPE tissues. Data were analysed using the CLC Bio Genomics Workbench and revealed systematic differences between FF and FFPE tissue-derived nucleic acid libraries. In spite of this, pairwise analysis of DNA Exome-Seq data showed concordance for 70-80 % of variants in FF and FFPE samples stored for fewer than three years. RNA-Seq data showed high correlation of expression profiles in FF/FFPE pairs (Pearson Correlations of 0.90 +/- 0.05), irrespective of storage time (up to 244 months) and tissue type. A common set of 1,494 genes was identified with expression profiles that were significantly different between paired FF and FFPE samples irrespective of tissue type. Our results are promising and suggest that NGS can be used to study FFPE specimens in both prospective and retrospective archive-based studies in which FF specimens are not available.

  Study EGAS00001000737

• Mesothelioma_Whole_Genomes

  Genomic architecture of mesothelioma parent study is project 925. This project is set up in parallel to project 925 in order to Whole genome sequence ten of the 59 tumours in that project.

  Study EGAS00001000830

• Myeloma_Follow_up_Pilot

  Targeted capture of exonic and intronic regions of interest for the study of genomic alterations in multiple myeloma.

  Study EGAS00001000743

• ICGC medulloblastoma whole genome sequencing data, ICGC release 16

  ICGC medulloblastoma whole genome sequencing data, ICGC release 16

  Study EGAS00001000744

• 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

• Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

  Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

  Study EGAS00001000750

• Chordoma_Extension__known_cancer_genes_

  Extension analysis to pursue candidate genes of interest in chordoma

  Study EGAS00001000895

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812