FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2593118632> ?p ?o ?g. }

• W2593118632 abstract "Abstract The genomic landscapes of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD) and other related myeloid malignancies are now amongst the best characterized cancer genomes. These malignancies share most of their somatic driver mutations, many of which have therapeutic and prognostic significance (Patel et al, NEJM 2012). Patient prognostication and clinical decision-making can be greatly facilitated by testing for these mutations in parallel with established diagnostic assays. Here, we describe and validate RISCL (Rearrangements, Indels, Substitutions, Copy number and Loss-of-heterozygosity), a novel methodological and bioinformatic tool for the molecular diagnosis of myeloid malignancies. This tool employs targeted DNA capture to simultaneously: 1) identify coding mutations in 49 genes, 2) detect the four most important translocations in AML and 3) derive genome-wide copy number and zygosity data. Samples & methods 1. Samples Genomic DNA was extracted from bone marrow samples of 62 patients with AML (n=86 samples, including 24 remission samples) and 68 patients with MDS; and from blood granulocytes and mononuclear cells from 5 cord blood samples and 18 adults with normal hematopoiesis. 2. cRNA baits and sequencing The bait library (Agilent) contained 53,613 probes to capture: 1) all exons from 49 genes 2) intronic breakpoint sites for PML-RARA, CBFb-MYH11 and RUNX1-RUNX1T1 and MLL breakpoints 3) 9958 SNPs (minor allele frequency 0.40-0.45) for genome wide copy number and zygosity analysis. Barcoded sequencing was performed using Illumina HiSeq 2000 (100bp paired-end). 3. Bioinformatic analysis We used bespoke bioinformatics for detecting coding substitutions and indels (MIDAS; Conte et al, Leukemia 2013), chromosomal translocations (SMALT-FIT), copy number analysis (Avadis software) and detection of specific mutations such as MLL-PTD and FLT3-ITD (in-house scripts). 4. Verification of results To validate the sensitivity and specificity of our approach, we compared our findings to conventional diagnostic data and are also validating 30% of randomly selected variants. Results A mean of 94% of targeted bases were covered at least by 30x. In AML samples, the four most common coding mutations identified affected NPM1 (n=10), CEBPA (n=8), IDH1 (n=8) and NRAS (n=7). By comparison to conventional diagnostics, we detected 5/5 IDH1R132, 4/4 CEBPA, 1/1 IDH2R172K and 8/9 NPM1 mutations. In MDS samples, the top four mutations affected TP53 (n=15), TET2 (n=13), SRSF2 (n=9), ASXL1 (n=8) and mutations affecting spliceosome genes (n=18) that were mutually exclusive, as previously described (Yoshida et al, Nature 2011). RISCL detected 100% of known translocations (28/28) in AML patients, namely CBFb-MYH11 (n=8/8), PML-RARA (n=9/9), RUNX1-RUNX1T1 (n=4/4) and rearrangements of MLL (n=7/7). In every case of MLL rearrangement the gene partner was identified and in one case with t(X;11) we identified a novel gene partner to MLL, DIAPH2. Furthermore, we identified one patient with an MLL rearrangement not identified at diagnosis. Copy number analysis efficiently detected known large chromosomal deletions or monosomies in chromosome 5 (18/18) and 7 (10/12). Overall 47/54 large deletions were detected using Avadis software. Furthermore in one MDS patient we were able to detect a submicroscopic heterozygous deletion in chromosome 4 which included TET2. However this method was much less sensitive for detecting trisomies (13/27 trisomies detected overall). The reasons for this disparity between detection of deletions and amplifications using a standardized depth of coverage algorithm are unclear, but may include subclonal mutations, selection of karyotypically abnormal cells during metaphase preparation or limitations of our bioinformatic analysis, which we are currently investigating. Figure 1 shows an example of the results of our holistic analysis using RISCL from an informative case of AML. In summary we describe RISCL, a novel powerful holistic NGS tool for detailed characterization of myeloid malignancies that can be used for patient stratification and a personalized approach to malignancy in the molecular era. The same approach can be extended to other malignancies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare." @default.
• W2593118632 created "2017-03-16" @default.
• W2593118632 creator A5000942690 @default.
• W2593118632 creator A5001423258 @default.
• W2593118632 creator A5007336607 @default.
• W2593118632 creator A5009403681 @default.
• W2593118632 creator A5027357638 @default.
• W2593118632 creator A5029251605 @default.
• W2593118632 creator A5037238553 @default.
• W2593118632 creator A5046521628 @default.
• W2593118632 creator A5051813765 @default.
• W2593118632 creator A5053750682 @default.
• W2593118632 creator A5055409889 @default.
• W2593118632 creator A5058146884 @default.
• W2593118632 creator A5074223916 @default.
• W2593118632 creator A5081020822 @default.
• W2593118632 creator A5086616451 @default.
• W2593118632 creator A5087840534 @default.
• W2593118632 creator A5087942382 @default.
• W2593118632 creator A5091438512 @default.
• W2593118632 date "2014-12-06" @default.
• W2593118632 modified "2023-10-01" @default.
• W2593118632 title "R.I.S.C.L: A Holistic Molecular Diagnostic Tool for Myeloid Malignancies" @default.
• W2593118632 doi "https://doi.org/10.1182/blood.v124.21.2342.2342" @default.
• W2593118632 hasPublicationYear "2014" @default.
• W2593118632 type Work @default.
• W2593118632 sameAs 2593118632 @default.
• W2593118632 citedByCount "0" @default.
• W2593118632 crossrefType "journal-article" @default.
• W2593118632 hasAuthorship W2593118632A5000942690 @default.
• W2593118632 hasAuthorship W2593118632A5001423258 @default.
• W2593118632 hasAuthorship W2593118632A5007336607 @default.
• W2593118632 hasAuthorship W2593118632A5009403681 @default.
• W2593118632 hasAuthorship W2593118632A5027357638 @default.
• W2593118632 hasAuthorship W2593118632A5029251605 @default.
• W2593118632 hasAuthorship W2593118632A5037238553 @default.
• W2593118632 hasAuthorship W2593118632A5046521628 @default.
• W2593118632 hasAuthorship W2593118632A5051813765 @default.
• W2593118632 hasAuthorship W2593118632A5053750682 @default.
• W2593118632 hasAuthorship W2593118632A5055409889 @default.
• W2593118632 hasAuthorship W2593118632A5058146884 @default.
• W2593118632 hasAuthorship W2593118632A5074223916 @default.
• W2593118632 hasAuthorship W2593118632A5081020822 @default.
• W2593118632 hasAuthorship W2593118632A5086616451 @default.
• W2593118632 hasAuthorship W2593118632A5087840534 @default.
• W2593118632 hasAuthorship W2593118632A5087942382 @default.
• W2593118632 hasAuthorship W2593118632A5091438512 @default.
• W2593118632 hasConcept C104317684 @default.
• W2593118632 hasConcept C122060243 @default.
• W2593118632 hasConcept C135763542 @default.
• W2593118632 hasConcept C138626823 @default.
• W2593118632 hasConcept C153209595 @default.
• W2593118632 hasConcept C206936463 @default.
• W2593118632 hasConcept C2778729363 @default.
• W2593118632 hasConcept C2779282312 @default.
• W2593118632 hasConcept C2780332060 @default.
• W2593118632 hasConcept C30481170 @default.
• W2593118632 hasConcept C502942594 @default.
• W2593118632 hasConcept C53226629 @default.
• W2593118632 hasConcept C54355233 @default.
• W2593118632 hasConcept C70721500 @default.
• W2593118632 hasConcept C86803240 @default.
• W2593118632 hasConceptScore W2593118632C104317684 @default.
• W2593118632 hasConceptScore W2593118632C122060243 @default.
• W2593118632 hasConceptScore W2593118632C135763542 @default.
• W2593118632 hasConceptScore W2593118632C138626823 @default.
• W2593118632 hasConceptScore W2593118632C153209595 @default.
• W2593118632 hasConceptScore W2593118632C206936463 @default.
• W2593118632 hasConceptScore W2593118632C2778729363 @default.
• W2593118632 hasConceptScore W2593118632C2779282312 @default.
• W2593118632 hasConceptScore W2593118632C2780332060 @default.
• W2593118632 hasConceptScore W2593118632C30481170 @default.
• W2593118632 hasConceptScore W2593118632C502942594 @default.
• W2593118632 hasConceptScore W2593118632C53226629 @default.
• W2593118632 hasConceptScore W2593118632C54355233 @default.
• W2593118632 hasConceptScore W2593118632C70721500 @default.
• W2593118632 hasConceptScore W2593118632C86803240 @default.
• W2593118632 hasLocation W25931186321 @default.
• W2593118632 hasOpenAccess W2593118632 @default.
• W2593118632 hasPrimaryLocation W25931186321 @default.
• W2593118632 hasRelatedWork W1529785358 @default.
• W2593118632 hasRelatedWork W1983432128 @default.
• W2593118632 hasRelatedWork W2493057054 @default.
• W2593118632 hasRelatedWork W2517151350 @default.
• W2593118632 hasRelatedWork W2534068539 @default.
• W2593118632 hasRelatedWork W2555953488 @default.
• W2593118632 hasRelatedWork W2557775062 @default.
• W2593118632 hasRelatedWork W2560450554 @default.
• W2593118632 hasRelatedWork W2564144955 @default.
• W2593118632 hasRelatedWork W2565318548 @default.
• W2593118632 hasRelatedWork W2568945947 @default.
• W2593118632 hasRelatedWork W2581316188 @default.
• W2593118632 hasRelatedWork W2581660450 @default.
• W2593118632 hasRelatedWork W2583229004 @default.
• W2593118632 hasRelatedWork W2587222030 @default.
• W2593118632 hasRelatedWork W2755028188 @default.
• W2593118632 hasRelatedWork W2777359937 @default.
• W2593118632 hasRelatedWork W3098812181 @default.
• W2593118632 hasRelatedWork W3112873670 @default.
• W2593118632 hasRelatedWork W3175386246 @default.

• next