1568 results for "Sweden+NDA+enforceability+one+party+signed"

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• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• Somatic mutations predict an aggressive phenotype in meningioma but do not drive grade progression

  A subset of meningiomas progress in histopathological grade and drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. Utilising a prospective database, we identified 10 patients with meningiomas that had undergone grade progression and for whom matched pre- and post-progression tissue (n=50 samples) was available for targeted next-generation sequencing. Mutations in NF2 were identified in 4/10 patients, 94% were non-skull base tumours. In one patient, three different NF2 mutations were identified in four tumours. NF2 mutated tumours showed large scale CNAs, with highly recurrent losses in 1p, 10, 22q, and frequent CNAs on chromosomes 2, 3 and 4. There was a correlation between grade and CNAs in a subset of patients. In two patients with sphenoid wing Grade III tumours without detected NF2 mutations, a STAT6-NAB2 inversion was identified. Two patients with tumours without detected NF2 mutations showed a combination of loss and high gain on chromosome 17q. Mutations in SETD2, TP53, TERT promoter and NF2 were not uniform across recurrent tumours and did not correspond with grade progression. Meningiomas that progress in grade generally have a mutational profile already detectable in the pre-progressed tumour, suggesting an aggressive phenotype . CNA profiling shows frequent alterations in NF2 mutated tumours compared to non NF2 mutated tumours and the pattern of CNAs may be associated with grade progression in a subset of cases.

  Study EGAS00001006585

• Microsatellite data show recent demographic expansions in sedentary but not in nomadic human populations in Africa and Eurasia.

  The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders, which could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area, which may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.

  Study EGAS00001000652

• Exome sequencing of uterine leiomyosarcomas

  Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. Aberrant expression of both TP53 and ATRX were associated with poor overall survival. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  Study EGAS00001001612

• RB Loss in Resistant EGFR Mutant Lung Adenocarcinomas that Transform to Small Cell Lung Cancer

  Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

  Study EGAS00001001102

• Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma. Details please contact lifuqiang@genomics and zhaoxin@genomics.cn.

  Background and aims: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) could reflect nearly the entire mutation spectrum in given tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC).Methods: Thirty-two multi-regional HCC samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS). ITH extent was measured by the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Matched cfDNAs were also analyzed by WES and TDS. Profiling efficiencies of single tumor specimen and cfDNA were compared and the one better depicted mutational landscape was selected to screen therapeutic targets.Results: We found variable extents of ITH in HCCs and observed branched and parallel evolution patterns. ITH level decreased at higher sequencing depth of TDS than that measured by WES (28.1% vs 34.9%, P < 0.01) but it remained unchanged upon additional samples analyzed. TDS of single tumor specimen detected an average of 70% the total mutations in HCC. Although more mutations were detected in cfDNA under TDS than WES, an average of 47.2% total HCC mutations uncovered by cfDNA suggested tissue outperform cfDNA and the latter may serve as alternative in profiling HCC genome. Consequently, TDS of single tumor tissue in 66 patients and cfDNAs in four unresectable HCCs identified 38.6% (26/66 and 1/4) patients bearing therapeutic targets.Conclusions: TDS of single tumor specimen could largely circumvent ITH to uncover mutations indicative of target therapy in HCC.

  Study EGAS00001002207

• Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

  Aberrant DNA repair processes are a hallmark of human tumours. How these deficiencies variously impact the genomes of ovarian cancer between and within histotypes remains unknown. We studied the whole genome pointmutation and structural variation patterns of 133 tumours (59 high grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell tumours (GCT)) as a substrate for class discovery in ovarian cancer. Ab-initio clustering of integrated point mutation and structural variation signatures revealed seven novel subgroups, comprising between and within histotype stratification. Prevalence of fold-back inversions (FBI) co-localised with high level amplification events divided HGSC into two prognostically significant subgroups. This finding was recapitulated in two additional independent cohorts (total n=576 cases), and transcended gene based mutation status and gene expression as prognostically relevant features of HGSC. CCOC were divided into one group harbouring a signature reflective of active genome editing via APOBEC enzymes (26%) and a complementary group with an age-relatedmutational signature. ENOC were divided intomicrosatellite instable (MSI) cases (28%) with a distinctmismatch repairmutation signature and an outlying mutation rate, with the remainder of cases distributed amongst the remaining six groups. We suggest the FBI, MSI, and APOBEC groups represent biologic strata that could direct treatment strategies. Taken together, our work establishes the efficacy of the somatic genome as a biomarker to stratify ovarian cancers, simultaneously identifying patients that may benefit from emerging therapeutics and distinct subgroups within classic ovarian cancer histotypes.

  Study EGAS00001002390

• 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

• Confirmation of a founder effect in a Northern European population (FRL) of a new beta-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA))

  Beta-thalassemia is a genetic disease caused by a defect in the production of the beta-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of 4 nucleotides in the first exon of beta-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the beta-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (9 generations). In order to determine whether this variant arose in this region of Northern-Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare beta-thalassemia variants have already been described in patients sampled in non-endemic regions but it is the first proof of a founder effect in Northern Europe. The new genetic panel FRL is under registration in EGA.

  Study EGAS00001000980

• Structure and evolution of double minutes in diagnosis and relapse brain tumors

  Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric tumor, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were resent in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment, but this was rare at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript absent in EST database and in about 700 brain tumors that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis / relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.

  Study EGAS00001003212