3995 results for "*geneti*"

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• Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour

  Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.

  Study EGAS00001001836

• Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population

  We recently showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at investigating the genetic determinants for glycated hemoglobin (HbA1C). We found no novel associations but saw that for 10 out of 15 known HbA1C loci that the effects in Greenlandic Inuit were similar to previously reported. One locus, ANK1, showed a significant ancestral population specific effect. Our results shed light on the genetics effects across ethnicites.

  Study EGAS00001002641

• Exome and RNA sequencing of relapsed TCF3-PBX1 t(1;19) acute lymphoblastic leukemia

  TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL while other drugs could be useful depending on the genetic context of individual patients.

  Study EGAS00001001876

• Novel regional age-associated DNA methylation changes within human common disease-associated loci

  Background: Advancing age progressively impacts on risk and severity of chronic disease. It also modifies the epigenome, with changes in DNA methylation, due to both random drift and variation within specific functional loci. Results: In a discovery set of 2,238 peripheral-blood genome-wide DNA methylomes (MeDIP-seq) aged 19-82 years, we identified 71 age-associated Differentially Methylated Regions (a-DMRs, p < 1.85 x 10-8) within the Linkage Disequilibrium (LD) blocks of the NIH Catalogue of published GWAS SNPs. This included 52 novel regions, 29 within loci not covered by 450k or 27k Illumina array, and with marked enrichment for Poised Promoters and Enhancers across multiple cell types. In a replication set of 2,084 DNA methylomes, 95.7% of the a-DMRs showed the same direction of ageing effect, with 80.3% and 53.3% replicated to p < 0.05 and p < 1.85 x 10-8, respectively. Conclusion: By analysing the functionally enriched disease and trait-associated regions of the human genome, we identified novel epigenetic ageing changes, which could be useful biomarkers or provide mechanistic insights into age-related common diseases.

  Study EGAS00001001910

• Inherited genetic predisposition to childhood acute lymphoblastic leukemia investigated using a genome wide association study.

  This series consists of summary data generated from a genome-wide association study (GWAS) investigating inherited genetic risk to childhood acute lymphoblastic leukemia (ALL). The GWAS comprised 784 cases recruited to the Medical Research Council UK ALL-2003 and ALL-97/99 trials and 7,385 controls. The data describe SNPtest association statistics from the case-control analysis.

  Study EGAS00001002809

• Genomic landscape of oral cancers (Illumina RNA-Seq)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001003237

• Next generation sequencing of sporadic schwannomatosis samples

  Schwannomatosis (MIM #162091) is characterized by the development of multiple schwannomas without vestibular nerve involvement (which is a characteristic of neurofibromatosis type 2 - NF2). In an effort to detect novel genetic alterations predisposing to schwannomatosis, we sequenced eight tumor-blood DNA pairs from de novo schwannomatosis patients. The results of our study are present in the paper "Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants" published in Acta Neuropathologica (PMID:25008767)

  Study EGAS00001000767

• Genomics of enteropathy associated T cell lymphoma (EATL)

  Enteropathy-associated T cell lymphoma (EATL) is a lethal and the most common neoplastic complication of celiac disease. In this study, we applied whole exome sequencing in 69 EATL tumors to define the genetic landscape of EATLs. The most frequently mutated gene in EATL was SETD2 (32% of cases), with loss of function mutations comprising a large proportion (41%) of those mutations. The JAK-STAT pathway was the most frequently mutated signaling pathway, with mutations in STAT5B being the most common, followed by JAK1, JAK3, STAT3, and the negative regulator of the pathway, SOCS1. We also identified mutations in NRAS and KRAS, as well as TP53 and TERT. Interestingly, the two types of EATL had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. Gene expression analysis of the two types of EATL identify robust differences in transcriptional profiles. We further modeled the effects of SETD2 loss in vivo by developing a T cell specific knockout mouse model. These mice manifested an expansion of γδ T cells that identify novel roles for SETD2 in T cell development and lymphomagenesis. Together, our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease, and may inform future classification schemes.

  Study EGAS00001001954

• Dynamics of multiple resistance mechanisms in plasma DNA and their clinical implications for NSCLC patients receiving EGFR-targeted therapies

  Background:The development of resistance mechanisms to targeted therapies is complicated by underlying tumour heterogeneity. When multiple resistance mechanisms co-exist, identifying the dominant driver(s) is critical for selection of treatment. Patients and methods:We studied the relative dynamics of multiple oncogenic drivers and resistance mechanisms in 50 patients with EGFR-mutant non-small cell lung cancer (NSCLC), during treatment with gefitinib and hydroxychloroquine (NCT00809237). We performed digital PCR and targeted deep sequencing of cell-free DNA from longitudinal plasma samples from all patients, and shallow whole genome sequencing of serial samples from three patients who underwent histological transformation to small-cell lung cancer (SCLC). ResultsEGFR activating mutations were assessed in tumour samples and accurately identified in plasma samples of 95% of patients (41/43). We identified additional mutations including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%), and PTEN (4/50, 8%), and tracked their relative levels in plasma. Patients with both TP53 and EGFR mutations detected in plasma pre-treatment tended to have worse overall survival than those where only EGFR was detected. The resistance-conferring EGFR T790M mutation was identified in 62% of the patients who progressed. Changes in relative levels of T790M and activating mutations in EGFR corresponded to clinical responses in two patients who were given sequential treatments. Patients who progressed without T790M detected in plasma had worse PFS during TKI continuation, and developed alternative resistance mechanisms, that could be identified in plasma DNA, including SCLC-associated copy number changes and TP53 mutations, that tracked with progression and response to subsequent therapies. Conclusion:Longitudinal analysis of multiple oncogenic drivers in ctDNA may help identifying dominant mechanisms of resistance to EGFR-targeted therapies, and highlight the importance of monitoring genetic events that are not direct drug targets but provide non-invasive molecular information that may guide clinical management.

  Study EGAS00001002908

• GENETIC HISTORY OF ITALY

  Recent scientific literature has highlighted the relevance of population genetic studies both for disease association-mapping in admixed populations and for understanding the history of human migrations. Deeper insight into the history of Italian population is critical for understanding the peopling of Europe. Because of its crucial position at the centre of the Mediterranean basin, the Italian peninsula has experienced a complex history of colonization and migration, whose genetic signatures are still present in contemporary Italians. In this study, we investigated genomic variation in the Italian population using 2.5 million single nucleotide polymorphisms (SNPs) in a sample of more than 300 unrelated Italian subjects with well-defined geographical origins. We combined several analytical approaches to interpret genome-wide data on 1,272 individuals from European, Middle Eastern, and North African populations. We detected three major ancestral components contributing different proportions across the Italian peninsula, and signatures of continuous gene flow within Italy, which has produced remarkable genetic variability among contemporary Italians. In addition, we have extracted novel details about the Italian population’s ancestry: we identified genetic signatures of major historical events in Europe and the Mediterranean basin from the Neolithic (e.g., peopling of Sardinia) to recent times (e.g., ‘barbarian invasion’ of Northern and Central Italy). These results are valuable for further genetic, epidemiological and forensic studies in Italy and in Europe.

  Study EGAS00001001458