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• W105454513 abstract "See related article on page 81 See related article on page 81 CME Accreditation Statement: This activity (“JMD 2013 CME Program in Molecular Diagnostics”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“JMD 2013 CME Program in Molecular Diagnostics”) for a maximum of 48 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity (“JMD 2013 CME Program in Molecular Diagnostics”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“JMD 2013 CME Program in Molecular Diagnostics”) for a maximum of 48 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. In the United States, acute myeloid leukemia (AML) develops in approximately 13,000 individuals annually and accounts for approximately 9000 cancer-related deaths per year.1American Cancer SocietyCancer Facts & Figures 2011. American Cancer Society, Atlanta, GA2011Google Scholar Although epidemiologically AML is considered a single disease, it is certainly not a uniform clinicopathologic entity. This fact is evidenced by the distinctly different outcomes observed in the clinical setting, with some patients responding well to chemotherapeutic regimens, others requiring hematopoietic stem cell transplants, and yet others rapidly dying of the disease. Although survival of patients with AML depends in part on tumor-extrinsic factors such as age and performance status, the major factors influencing prognosis are the molecular characteristics of the tumor cells themselves, in particular translocations and other genetic mutations, epigenetic abnormalities, and mRNA and miRNA expression.2Dixon-McIver A. East P. Mein C.A. Cazier J.B. Molloy G. Chaplin T. Andrew Lister T. Young B.D. Debernardi S. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia.PLoS One. 2008; 3: e2141Crossref PubMed Scopus (227) Google Scholar, 3Figueroa M.E. Lugthart S. Li Y. Erpelinck-Verschueren C. Deng X. Christos P.J. Schifano E. Booth J. van Putten W. Skrabanek L. Campagne F. Mazumdar M. Greally J.M. Valk P.J. Löwenberg B. Delwel R. Melnick A. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.Cancer Cell. 2010; 17: 13-27Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar, 4Grimwade D. Mrózek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia.Hematol Oncol Clin North Am. 2011; 25 (vii): 1135-1161Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 5Patel J.P. Gonen M. Figueroa M.E. Fernandez H. Sun Z. Racevskis J. Van Vlierberghe P. Dolgalev I. Thomas S. Aminova O. Huberman K. Cheng J. Viale A. Socci N.D. Heguy A. Cherry A. Vance G. Higgins R.R. Ketterling R.P. Gallagher R.E. Litzow M. van den Brink M.R. Lazarus H.M. Rowe J.M. Luger S. Ferrando A. Paietta E. Tallman M.S. Melnick A. Abdel-Wahab O. Levine R.L. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.N Engl J Med. 2012; 366: 1079-1089Crossref PubMed Scopus (1452) Google Scholar, 6Valk P.J. Verhaak R.G. Beijen M.A. Erpelinck C.A. Barjesteh van Waalwijk van Doorn-Khosrovani S. Boer J.M. Beverloo H.B. Moorhouse M.J. van der Spek P.J. Löwenberg B. Delwel R. Prognostically useful gene-expression profiles in acute myeloid leukemia.N Engl J Med. 2004; 350: 1617-1628Crossref PubMed Scopus (1106) Google Scholar Indeed, AML can be divided into subcategories based solely on the genomic, epigenomic, or transcriptomic characteristics of the neoplastic cells. Such subgroups are associated with significantly distinct outcomes, indicating that the molecular changes involved in AML unequivocally contribute to overall prognosis. Thus, identifying the spectrum of prognostically important aberrancies that occur within the leukemic cells is an area of intense basic research, and the use of clinical assays that probe these abnormalities is required for optimal treatment of patients with these malignancies. The first recognized and best-studied recurrent genetic lesions in AML are large unsubtle chromosomal anomalies, which are usually detected by metaphase cytogenetic analysis.4Grimwade D. Mrózek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia.Hematol Oncol Clin North Am. 2011; 25 (vii): 1135-1161Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar These include translocations and inversions such as t(8;21), inv(16), and t(15;17), which confer a relatively good prognosis, and chromosomal gains and losses such as monosomy 7, which confers a poor prognosis. However, some AML cases do not display any abnormalities recognized by either traditional karyotyping or by its younger and more sensitive cousin, fluorescence in situ hybridization (FISH), and these cases with normal karyotypes account for approximately 40% to 50% of AML diagnoses.7Morrissette J.J. Bagg A. Acute myeloid leukemia: conventional cytogenetics, FISH, and moleculocentric methodologies.Clin Lab Med. 2011; 31 (x): 659-686Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Despite the absence of karyotypic abnormalities, normal-karyotype AMLs are clearly not genetically normal, and they harbor mutations that distinguish the malignant cells from their physiological counterparts. In the past few years, numerous recurrent mutations that are too small to be detected by karyotyping or FISH have been discovered. This ever-expanding list includes mutations in FLT3, NPM1, CEBPA, WT1, KRAS, TET2, DNMT3A, IDH1, IDH2, ASXL1, and PHF6.5Patel J.P. Gonen M. Figueroa M.E. Fernandez H. Sun Z. Racevskis J. Van Vlierberghe P. Dolgalev I. Thomas S. Aminova O. Huberman K. Cheng J. Viale A. Socci N.D. Heguy A. Cherry A. Vance G. Higgins R.R. Ketterling R.P. Gallagher R.E. Litzow M. van den Brink M.R. Lazarus H.M. Rowe J.M. Luger S. Ferrando A. Paietta E. Tallman M.S. Melnick A. Abdel-Wahab O. Levine R.L. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.N Engl J Med. 2012; 366: 1079-1089Crossref PubMed Scopus (1452) Google Scholar, 8Watt C.D. Bagg A. Molecular diagnosis of acute myeloid leukemia.Expert Rev Mol Diagn. 2010; 10: 993-1012Crossref PubMed Scopus (10) Google Scholar Many of these mutations have been demonstrated to have prognostic and sometimes related diagnostic implications for patients with AML. As a result, the latest edition of the World Health Organization fascicle on the classification of hematopoietic neoplasms includes provisional AML entities defined by mutations in NPM1 and CEBPA, and recognizes the importance of testing for FLT3 mutations (although the classification does not elevate AML with FLT3 mutations to an entity).9Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. Thiele J. Vardiman J.W. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. ed 4. IARC Press, Lyon2008: 118-123Google Scholar The latest National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML recommend testing for mutations in these three genes at diagnosis.10NCCN Clinical Practice Guidelines in OncologyAcute Myeloid Leukemia Version 2.2012. National Comprehensive Cancer Network, Fort Washington, PA2012Google Scholar In this regard, the article by Spencer et al11Spencer D.H. Abel H.J. Lockwood C.M. Payton J.E. Szankasi P. Kelley T.W. Kulkarni S. Pfeifer J.D. Duncavage E.J. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data.J Mol Diagn. 2013; 15: 81-93Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar in this issue of The Journal of Molecular Diagnostics is significant in that it outlines a novel method, based on next-generation sequencing (NGS), by which FLT3 mutations can be detected. Although their report focuses solely on FLT3 mutation detection, the main implication of the article is that other mutations, such as those in NPM1 and CEBPA, could be detected simultaneously. The fms-related tyrosine kinase 3 gene (FLT3) encodes a class III receptor tyrosine kinase that is required for normal hematopoiesis.12Mackarehtschian K. Hardin J.D. Moore K.A. Boast S. Goff S.P. Lemischka I.R. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.Immunity. 1995; 3: 147-161Abstract Full Text PDF PubMed Scopus (484) Google Scholar Recurrent mutations in the FLT3 gene have been found in approximately 20% of AML cases overall, and in approximately 30% of normal-karyotype AML cases.7Morrissette J.J. Bagg A. Acute myeloid leukemia: conventional cytogenetics, FISH, and moleculocentric methodologies.Clin Lab Med. 2011; 31 (x): 659-686Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar These mutations fall into two broad categories: internal tandem duplications (ITDs) within the juxtamembrane domain and point mutations within the kinase domain.13Foran J.M. New prognostic markers in acute myeloid leukemia: perspective from the clinic.Hematology Am Soc Hematol Educ Program. 2010; 2010: 47-55Crossref PubMed Scopus (103) Google Scholar Although both types of mutations render the kinase constitutively active, only the ITD mutation has been definitively shown to correlate with prognosis. The presence of an FLT3 ITD confers a poor prognosis, and patients with an FLT3 ITD usually require hematopoietic stem cell transplant, because most are not expected to be to be cured with chemotherapy alone.14Mead A.J. Gale R.E. Hills R.K. Gupta M. Young B.D. Burnett A.K. Linch D.C. Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease.Blood. 2008; 112: 444-445Crossref PubMed Scopus (30) Google Scholar A few recent studies have shown that the FLT3 ITD protein is indeed a leukemogenic molecule that drives the formation of aggressive tumors. FLT3 ITD can cause aggressive AML in mice of a specific genetic background with 100% penetrance.15Greenblatt S. Li L. Slape C. Nguyen B. Novak R. Duffield A. Huso D. Desiderio S. Borowitz M.J. Aplan P. Small D. Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model.Blood. 2012; 119: 2883-2894Crossref PubMed Scopus (54) Google Scholar Additionally, FLT3 ITD-positive patients treated with an FLT3 inhibitor who become resistant to treatment acquire activating mutations within the FLT3 kinase domain.16Smith C.C. Wang Q. Chin C.S. Salerno S. Damon L.E. Levis M.J. Perl A.E. Travers K.J. Wang S. Hunt J.P. Zarrinkar P.P. Schadt E.E. Kasarskis A. Kuriyan J. Shah N.P. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.Nature. 2012; 485: 260-263Crossref PubMed Scopus (548) Google Scholar However, because i) not all of the leukemic blasts from a single FLT3 ITD-positive patient harbor the insertion,17Gale R.E. Green C. Allen C. Mead A.J. Burnett A.K. Hills R.K. Linch D.C. Medical Research Council Adult Leukaemia Working PartyThe impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.Blood. 2008; 111: 2776-2784Crossref PubMed Scopus (575) Google Scholar because ii) the FLT3 ITD can be present at initial diagnosis and subsequently lost at relapse, or vice versa,18Kottaridis P.D. Gale R.E. Langabeer S.E. Frew M.E. Bowen D.T. Linch D.C. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors.Blood. 2002; 100: 2393-2398Crossref PubMed Scopus (260) Google Scholar and because iii) FLT3 ITD tumors do not fit into distinct tumor subclasses in unbiased clustering analyses,3Figueroa M.E. Lugthart S. Li Y. Erpelinck-Verschueren C. Deng X. Christos P.J. Schifano E. Booth J. van Putten W. Skrabanek L. Campagne F. Mazumdar M. Greally J.M. Valk P.J. Löwenberg B. Delwel R. Melnick A. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.Cancer Cell. 2010; 17: 13-27Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar the FLT3 ITD is thought to be a secondary, rather than an initiating, mutation. It is therefore not, as we have already noted, afforded designation as a separate entity in the World Health Organization classification of AML.9Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. Thiele J. Vardiman J.W. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. ed 4. IARC Press, Lyon2008: 118-123Google Scholar Regardless of the underlying biology of FLT3 mutations, it is apparent that determination of FLT3 ITD status has prognostic as well as therapeutic implications for patients with AML. Thus, FLT3 testing is routinely performed on diagnostic AML specimens. Typically, the assay is performed by PCR using primers that flank the site of the potential ITD, followed by capillary electrophoresis.19Bubán T. Koczok K. Földesi R. Szabó G. Sümegi A. Tanyi M. Szerafin L. Udvardy M. Kappelmayer J. Antal-Szalmás P. Detection of internal tandem duplications in the FLT3 gene by different electrophoretic methods.Clin Chem Lab Med. 2011; 50: 301-310PubMed Google Scholar Not only can this test identify the FLT3 ITD, but it also allows for determination of the length of the inserted sequence as well as an approximate allelic ratio of FLT3 ITD to wild-type FLT3, both of which have been shown to affect patient outcome.17Gale R.E. Green C. Allen C. Mead A.J. Burnett A.K. Hills R.K. Linch D.C. Medical Research Council Adult Leukaemia Working PartyThe impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.Blood. 2008; 111: 2776-2784Crossref PubMed Scopus (575) Google Scholar The molecular test for FLT3 status is performed as a single, independent assay. Additional separate assays are required to determine whether the tumor has a recurrent translocation, whether it harbors chromosomal gains or losses, and whether other prognostically important loci are mutated, such as NPM1 and CEBPA (or many other novel genetic candidates). As the number of loci that influence prognosis and treatment of AML expands, such monoplex assays are becoming increasingly inefficient and costly. Thus, there is certainly a growing need to develop and validate clinical assays that can probe multiple mutations simultaneously. Consolidation of numerous independent analyses into a single multiplexed assay could reduce i) the cost of performing molecular tests, ii) the amount of patient specimen needed for molecular prognostication, iii) the turnaround time for reporting test results, and iv) perhaps also sample misidentification. A number of proprietary tests (eg, those that perform multiplex RT-PCR for seven recurrent acute leukemia translocations) have capitalized on this need for multiple mutation analyses.20King R.L. Naghashpour M. Watt C.D. Morrissette J.J. Bagg A. A comparative analysis of molecular genetic and conventional cytogenetic detection of diagnostically important translocations in more than 400 cases of acute leukemia, highlighting the frequency of false-negative conventional cytogenetics.Am J Clin Pathol. 2011; 135: 921-928Crossref PubMed Scopus (26) Google Scholar Next-generation sequencing, in which DNA sequence for multiple loci (or indeed the entire genome) can be obtained simultaneously with a single procedure is definitely a modality that can be used to probe multiple loci simultaneously. Not surprisingly, NGS serves as the basis for rapidly evolving assays to meet this diagnostic need. In this issue, Spencer et al11Spencer D.H. Abel H.J. Lockwood C.M. Payton J.E. Szankasi P. Kelley T.W. Kulkarni S. Pfeifer J.D. Duncavage E.J. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data.J Mol Diagn. 2013; 15: 81-93Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar show the feasibility of using a NGS approach to evaluate the presence of FLT3 ITDs in tumor samples. To test this methodology, the authors initially obtained DNA from peripheral blood, bone marrow, and formalin-fixed tissue samples. They then randomly fragmented the DNA, ligated specific adapters to the ends of these fragments, and amplified the ligated products. Amplified products from specific genomic locations were then selected from the entire genomic pool by hybridization to biotinylated cRNA capture probes that were then isolated by binding to streptavidin-coated magnetic beads. After enrichment for the captured fragments, the targeted libraries were subjected to standard NGS sequencing protocols using a HiSeq 2000 sequencing system (Illumina, San Diego, CA). Primary analysis resulted in base calls and corresponding quality scores for each of the millions of reads generated. The resulting data were aligned to the reference human genome sequence (hg19, NCBI build GRCh) using Novalign (Novocraft, Selangor, Malaysia) and were queried for the presence of FLT3 ITDs using multiple analytic algorithms. The authors compared the results they obtained from NGS analysis to those obtained from the standard FLT3 ITD analysis (performed by PCR followed by capillary electrophoresis). Using this protocol, the authors first assessed the number of sequence reads they obtained from the FLT3 area of interest (exons 14 and 15 and the intervening intron of the FLT3 gene). Regardless of ITD status, an average read depth of approximately 2000 reads was obtained, allowing for statistical robustness in the subsequent analysis. Variant calls from the alignment data were assessed using a number of publicly available analysis packages (including GATK, SAMtools, Maq, Dindel, SLOPE, BreakDancer, and Pindel), to determine which tools could identify FLT3 ITDs accurately. Pindel, which allows for localized reassembly and alignment of read pairs with only one end anchored, was the only tool that could consistently determine ITD status, and it did so extraordinarily well. Of 10 cases known to harbor an FLT3 ITD, Pindel identified an insertion in all of them. Furthermore, Pindel was able to detect ITDs in cases in which two or three distinct ITDs were present. Although in a case known to harbor two independent ITDs the software algorithm failed to detect one of them, in another case it did reveal a previously unrecognized ITD. When used to test an additional 41 samples, the NGS assay followed by Pindel analysis correctly identified all 10 samples with a known FLT3 ITD and further identified two cases with a previously undetected (and subsequently confirmed) ITD at an allelic ratio of <0.05. Thus, the overall diagnostic sensitivity and specificity were both 100%. The authors also used unpublished algorithms (custom scripts executing Phrap assembly software) that rely on de novo assembly of overlapping reads to identify FLT3 ITDs. Similar to the analysis using Pindel, the overall sensitivity and specificity of this approach were remarkable. All cases with ITDs initially determined by PCR were identified by this method, and all ITD-negative cases were shown to be negative. Only a single case that was positive by both Pindel and subsequent reanalysis by PCR was missed with this algorithmic approach. Despite the one error, this method of analysis showed remarkable robustness for ITD status determination. Because both the length of the ITD and the allelic frequency of the ITD have been shown to correlate with overall outcome in patients with AML, the authors also compared their NGS results for ITD length and relative amounts with those determined by PCR and capillary electrophoresis. In terms of ITD size, both Pindel and the de novo assembly algorithm correlate highly with the PCR results. Unfortunately, a few outliers, some of which are rather extreme, were observed for both methods. A lower correlation was seen for allelic ratio with Pindel than with the de novo assembly algorithm, compared with PCR, and one extreme outlier was noted for Pindel. Both methods generally underestimated the ITD allele fraction, and for some cases in which the allele fraction was between 0.2 and 0.4, both Pindel and de novo assembly reported allelic ratios of less than 0.1. The lower than expected allelic ratio is not entirely surprising, given that the FLT3 ITD detection rate can be limited by the ability to map mutant reads to this region successfully. This would, in turn, lead to a falsely decreased ITD-to-wild type allelic ratio. Despite these discrepancies in ITD length and allelic ratio, the results obtained by Spencer et al11Spencer D.H. Abel H.J. Lockwood C.M. Payton J.E. Szankasi P. Kelley T.W. Kulkarni S. Pfeifer J.D. Duncavage E.J. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data.J Mol Diagn. 2013; 15: 81-93Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar are quite remarkable. Their study is, to date, the most extensive analysis of the reliability of NGS to determine FLT3 ITD status. In a recent study, Thol et al21Thol F. Kölking B. Damm F. Reinhardt K. Klusmann J.H. Reinhardt D. von Neuhoff N. Brugman M.H. Schlegelberger B. Suerbaum S. Krauter J. Ganser A. Heuser M. Next-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations.Genes Chromosomes Cancer. 2012; 51: 689-695Crossref PubMed Scopus (97) Google Scholar obtained similar results using completely different locus capture, sequencing methodology, and analytical algorithms, albeit on a smaller cohort of samples. Given the primacy of the report by Spencer et al,11Spencer D.H. Abel H.J. Lockwood C.M. Payton J.E. Szankasi P. Kelley T.W. Kulkarni S. Pfeifer J.D. Duncavage E.J. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data.J Mol Diagn. 2013; 15: 81-93Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar along with the near-perfect sensitivity and specificity of the assay, these investigators have set the standard by which both preanalytic NGS methods and analytic algorithms for ITD determination will be judged. Moreover, the study suggests that NGS, followed by either Pindel or a de novo sequence assembly of the FLT3 region, is sufficiently robust to be used as a clinical assay for FLT3 ITD assessment. Because the number of samples used in the study was rather small, and for an unknown reason (perhaps because the DNA was already prepared?) many of the ITD-negative cases were lung adenocarcinomas, similar studies should be repeated on larger data sets that contain only AML samples. Importantly, the sequencing of the FLT3 region containing the ITD was performed simultaneously with a protocol used to detect point mutations in 26 tumor-associated genes. This combination of assays, point mutation determination, and ITD status analysis suggests that NGS can be used as a multiplex analysis platform in which multiple mutations (and, more importantly, multiple mutation types) can be detected from a single sample and with a single procedure. Although one would not expect the addition of the FLT3 ITD to affect the detection of mutations in the other genes, the authors do not present data to confirm this hypothesis. The ability to perform the two types of assays simultaneously would represent an exciting advance in the molecular diagnosis of AML. Although NGS performed reasonably well with regards to determining ITD length and allelic ratios, the discrepancies noted, especially the extreme outliers, are of some concern and may limit the utility of NGS in cases in which precise allelic ratio or ITD length must be determined to direct specific treatment. In these rare but likely cases, confirmatory PCR and capillary electrophoresis can be performed. An interesting implication that can be deduced from the approach used in this study is that important information regarding relatively large alterations of genomic structure can be gleaned from NGS data if appropriate algorithmic pipelines are thoughtfully used. Indeed, the authors state in their discussion that cases with ITDs had a number of indicators in their FLT3 sequences, such as read pairs in which only one end of the sequence aligned to the reference sequence. Although these indicators could be used to identify other regions where insertions exist, they could also potentially be used to identify the recurrent translocations that occur in AML; for example, sequence reads that align only partially to RUNX1 might herald a t(8;21) translocation. Thus, testing for recurrent translocations, FLT3 ITD, and numerous point mutations, all of which are currently performed as independent assays, could all be analyzed simultaneously. Spencer et al11Spencer D.H. Abel H.J. Lockwood C.M. Payton J.E. Szankasi P. Kelley T.W. Kulkarni S. Pfeifer J.D. Duncavage E.J. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data.J Mol Diagn. 2013; 15: 81-93Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar show that this possibility of simultaneous mutational-type testing in molecular diagnosis of leukemias has become a very attainable and likely very imminent reality. Detection of FLT3 Internal Tandem Duplication in Targeted, Short-Read-Length, Next-Generation Sequencing DataThe Journal of Molecular DiagnosticsVol. 15Issue 1PreviewA recurrent somatic mutation frequently found in cytogenetically normal acute myeloid leukemia (AML) is internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3). This mutation is generally detected in the clinical laboratory by PCR and electrophoresis-based product sizing. As the number of clinically relevant somatic mutations in AML increases, it becomes increasingly attractive to incorporate FLT3 ITD testing into multiplex assays for many somatic mutations simultaneously, using next-generation sequencing (NGS). Full-Text PDF Open Access" @default.
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• W105454513 isRetracted "false" @default.
• W105454513 magId "105454513" @default.
• W105454513 workType "article" @default.