FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2552459203> ?p ?o ?g. }

• W2552459203 abstract "Abstract Introduction: B cell precursor acute lymphoblastic leukemia (BCP-ALL) represents the largest immunophenotypically defined subgroup of adult ALL. Yet, targeted therapies are assigned only to the minority of patients, whereas druggable lesions for the majority of adult BCP-ALL are still unknown. Thus, it remains necessary to explore their genomic landscape to unravel molecular alterations suitable for targeted therapies. We analyzed the mutational pattern of 206 candidate genes in adult BCP-ALL patients at diagnosis and matched relapse samples, focusing on therapeutically targetable alterations and their clonal evolution. Patients and methods : We performed targeted resequencing on diagnostic samples of patients with BCR-ABL negative BCP-ALL (n=89) as well as matched relapse samples (n=53). The mean age at first diagnosis was 44 years (range 17 - 79). Relapses were categorized as early (> 18 months from diagnosis, n=33) or late (< 18 months, n=20). All patients were enrolled on trials of the German Acute Lymphoblastic Leukemia Multicenter Study Group (GMALL). The targeted region comprised 206 genes known to be frequently mutated in leukemia and relevant in normal hematopoiesis. Customized biotinylated RNA oligo pools (SureSelect, Agilent) were used to select the targeted regions. We performed 100-bp paired-end sequencing on an Illumina Genome HiSeq1500 sequencing system. For a variant call, we required at least a read depth of 30 and a variant allele frequency (VAF) of 10%. We obtained an average coverage of 825 reads for the target region with over 98 percent of the targeted region been covered with a minimum of 30 reads. After exclusion of polymorphism annotated in dbSNP135, 625 protein changing single nucleotide variations and small indels were identified. 139 of the 206 target genes were mutated at least once. Results: On average three (median 3.0, range 1-12) genes were mutated in the 89 diagnostic BCP-ALL samples. The most frequent mutations included alterations in NRAS (18%), PAX5 (16%), TP53 (9%), JAK1/2 (8%) and IKZF1 (6%). Categorizing mutated genes according to their functional annotation revealed that 44 (49%) of patients harbored at least one mutation affecting epigenetic regulation, followed by adhesion/matrix proteins (48%), transcription factors (46%), RAS pathway genes (29%), kinase signaling (28%), and p53/cell cycle regulation (26%). Four (KMT2D, SETD2, KDM6A, KDM6B) of the twelve most frequently mutated genes, affecting 30 patients (34%), were epigenetic regulators specifically involved in histone methylation. Mutations in these genes were nearly mutually exclusive, suggesting their functional redundancy in this context. For 53 of the 89 patients matched relapse samples were available, showing a median frequency of 4.0 (range 1-36) mutated genes per sample. The frequency of mutations across gene families was similar compared to diagnostic samples, except for those involved in epigenetic regulation that showed a higher mutation rate at relapse (55%). In 68% of matched relapse samples, mutational gains and losses indicated mechanisms of clonal evolution. Among 28 patients (53%), which gained at least one mutation, the Lysine-Specific Methyltransferase 2D (KMT2D) was the most frequently affected gene with 7 patients acquiring KMT2D alterations at relapse. Other methyl-transferases (SETD2, KMT2C) as well as demethylases (KDM5A, KDM6A, KDM6B) acquired novel mutations at relapse, contributing to a total of 11 patients (21%) that gained alterations in histone methylation regulators. Notably, mutations in methylation regulators were only gained, but not lost at relapse. Nine of these 11 patients suffered an early relapse, implicating a selection advantage for clones harboring mutations in methylation regulating genes and their involvement in a more aggressive course of the disease. Conclusion: We describe for the first time a highly heterogeneous genomic mutational spectrum in adult BCP-ALL. A high mutation rate at diagnosis and further increase at relapse identified regulators of histone methylation as a most prominent target of recurrent alterations. Functional studies are needed to determine the direct biological consequence of these alterations, facilitating targeted therapeutic interventions with epigenetically active compounds. Disclosures Baldus: Novartis: Research Funding." @default.
• W2552459203 created "2016-11-30" @default.
• W2552459203 creator A5010697303 @default.
• W2552459203 creator A5012760420 @default.
• W2552459203 creator A5012871893 @default.
• W2552459203 creator A5023567299 @default.
• W2552459203 creator A5029609160 @default.
• W2552459203 creator A5030808762 @default.
• W2552459203 creator A5035426042 @default.
• W2552459203 creator A5037185840 @default.
• W2552459203 creator A5039023052 @default.
• W2552459203 creator A5044553314 @default.
• W2552459203 creator A5047397104 @default.
• W2552459203 creator A5047565991 @default.
• W2552459203 creator A5063965232 @default.
• W2552459203 creator A5066213019 @default.
• W2552459203 creator A5067318724 @default.
• W2552459203 creator A5069430515 @default.
• W2552459203 creator A5075073484 @default.
• W2552459203 date "2015-12-03" @default.
• W2552459203 modified "2023-10-09" @default.
• W2552459203 title "Genomic Profiling Reveals Gain of Mutations in Histone Methylation Regulators in Relapsed Adult B Cell Precursor ALL" @default.
• W2552459203 doi "https://doi.org/10.1182/blood.v126.23.2625.2625" @default.
• W2552459203 hasPublicationYear "2015" @default.
• W2552459203 type Work @default.
• W2552459203 sameAs 2552459203 @default.
• W2552459203 citedByCount "0" @default.
• W2552459203 crossrefType "journal-article" @default.
• W2552459203 hasAuthorship W2552459203A5010697303 @default.
• W2552459203 hasAuthorship W2552459203A5012760420 @default.
• W2552459203 hasAuthorship W2552459203A5012871893 @default.
• W2552459203 hasAuthorship W2552459203A5023567299 @default.
• W2552459203 hasAuthorship W2552459203A5029609160 @default.
• W2552459203 hasAuthorship W2552459203A5030808762 @default.
• W2552459203 hasAuthorship W2552459203A5035426042 @default.
• W2552459203 hasAuthorship W2552459203A5037185840 @default.
• W2552459203 hasAuthorship W2552459203A5039023052 @default.
• W2552459203 hasAuthorship W2552459203A5044553314 @default.
• W2552459203 hasAuthorship W2552459203A5047397104 @default.
• W2552459203 hasAuthorship W2552459203A5047565991 @default.
• W2552459203 hasAuthorship W2552459203A5063965232 @default.
• W2552459203 hasAuthorship W2552459203A5066213019 @default.
• W2552459203 hasAuthorship W2552459203A5067318724 @default.
• W2552459203 hasAuthorship W2552459203A5069430515 @default.
• W2552459203 hasAuthorship W2552459203A5075073484 @default.
• W2552459203 hasConcept C104317684 @default.
• W2552459203 hasConcept C138626823 @default.
• W2552459203 hasConcept C143998085 @default.
• W2552459203 hasConcept C150194340 @default.
• W2552459203 hasConcept C190727270 @default.
• W2552459203 hasConcept C2780235182 @default.
• W2552459203 hasConcept C2780833115 @default.
• W2552459203 hasConcept C502942594 @default.
• W2552459203 hasConcept C54355233 @default.
• W2552459203 hasConcept C71924100 @default.
• W2552459203 hasConcept C86803240 @default.
• W2552459203 hasConceptScore W2552459203C104317684 @default.
• W2552459203 hasConceptScore W2552459203C138626823 @default.
• W2552459203 hasConceptScore W2552459203C143998085 @default.
• W2552459203 hasConceptScore W2552459203C150194340 @default.
• W2552459203 hasConceptScore W2552459203C190727270 @default.
• W2552459203 hasConceptScore W2552459203C2780235182 @default.
• W2552459203 hasConceptScore W2552459203C2780833115 @default.
• W2552459203 hasConceptScore W2552459203C502942594 @default.
• W2552459203 hasConceptScore W2552459203C54355233 @default.
• W2552459203 hasConceptScore W2552459203C71924100 @default.
• W2552459203 hasConceptScore W2552459203C86803240 @default.
• W2552459203 hasLocation W25524592031 @default.
• W2552459203 hasOpenAccess W2552459203 @default.
• W2552459203 hasPrimaryLocation W25524592031 @default.
• W2552459203 hasRelatedWork W2406566860 @default.
• W2552459203 hasRelatedWork W2475831982 @default.
• W2552459203 hasRelatedWork W2530920543 @default.
• W2552459203 hasRelatedWork W2550307446 @default.
• W2552459203 hasRelatedWork W2552737367 @default.
• W2552459203 hasRelatedWork W2556307665 @default.
• W2552459203 hasRelatedWork W2557353056 @default.
• W2552459203 hasRelatedWork W2562257842 @default.
• W2552459203 hasRelatedWork W2578858472 @default.
• W2552459203 hasRelatedWork W2584938961 @default.
• W2552459203 hasRelatedWork W2586567058 @default.
• W2552459203 hasRelatedWork W2588014963 @default.
• W2552459203 hasRelatedWork W2589472232 @default.
• W2552459203 hasRelatedWork W2611878485 @default.
• W2552459203 hasRelatedWork W2612547744 @default.
• W2552459203 hasRelatedWork W2979315058 @default.
• W2552459203 hasRelatedWork W2979471952 @default.
• W2552459203 hasRelatedWork W3029780056 @default.
• W2552459203 hasRelatedWork W3120279246 @default.
• W2552459203 hasRelatedWork W3193063011 @default.
• W2552459203 isParatext "false" @default.
• W2552459203 isRetracted "false" @default.
• W2552459203 magId "2552459203" @default.
• W2552459203 workType "article" @default.