15 research outputs found
Developmental Spelling in Fourth Grade: An Analysis of What Poor Readers Do
Since Carol Chomsky (1971a, 1971b) and Charles Read (1971) published their pioneer reports on the development of writing behaviors in young children, examinations of the developmental or invented spellings of emergent writers have contributed to changes in emphases in early literacy instruction. Before that time educators seldom advocated writing experiences for children before they learned to read (Adams, 1990). During the past twenty-five years, there have been careful descriptions and analyses of the developmental stages and strategies of young children who experiment with and work through patterns of spelling while discovering written language. As a result of this body of work, more teachers have learned to decipher and assess the development of spellings of preschoolers and primary grade students. The increased ability to understand beginning attempts with print of the youngest writers has no doubt contributed to the encouragement of story writing, journals, and other writing activities from the earliest school years. Fortunately, the increase in opportunities to write also enhances the development of phonemic awareness and word recognition, both of which are predictors of future reading success (Gill, 1992; Juel, Griffith, and Gough, 1986; Perfetti, 1985; Tunmer and Nesdale, 1985)
Oral Participation in Shared Reading and Writing By Limited English Proficient Students in a Multiethnic Class Setting
Meeting the educational needs of students with limited English proficiency is a challenge that is changing and will continue to change the direction of educational programs. There has been a huge influx of limited English proficient (LEP) students across all geographic regions of the United States (United States Department of Education, 1992). Of the 25 largest school districts in the country, 23 have a majority of minority students (Multicultural Education Review Task Force, 1991). The impact of this increase in LEP students has resulted in individual states and school districts examining their resources, priorities, and curricula to meet their needs
Developing Understanding of Research-based Pedagogy with Preservice Teachers: An Instrumental Case Study
Preservice teachers have difficulty incorporating research-based instructional strategies and often revert to those observed during their own school years. This study describes how preservice teachers used a framework of planning, implementation, feedback, and reflection to try research-based teaching practices from their methods courses and examine their notions of effective pedagogy. This instrumental case study of 50 preservice teachers in a two-day-per-week field experience includes intensive interviews of six selected students. Findings include kinds of support reported as helpful in implementing new instructional strategies, difficulties experienced in the implementation of strategies, and new understandings of effective teaching during use of the framework. Participants used the framework to identify and examine preconceived notions of effective pedagogy, but also revealed some unplanned learnings
Elimination of bioweapons agents from forensic samples during extraction of human DNA
Collection of DNA for genetic profiling is a powerful means for the identification of individuals responsible for crimes and terrorist acts. Biologic hazards, such as bacteria, endospores, toxins, and viruses, could contaminate sites of terrorist activities and thus could be present in samples collected for profiling. The fate of these hazards during DNA isolation has n
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Mutational Spectrum of Myelodysplastic Syndrome Malignancies Revealed by Whole Exome Sequencing
Abstract
Abstract 307
Whole-exome (WES) sequencing revealed tremendous mutational heterogeneity in leukemia. While WES can be applied for discovery, it also has potential as a diagnostic tool that can overcome the shortcomings of current methods. We theorized that, in addition to mutation discovery, systematic application of WES in MDS may reveal distinct mutational patterns allowing for new molecular classification.
We performed WES in 116 paired exomes, including MDS (n=57), MDS/MPN (n=36), and sAML (n=23). We also included comparative analysis with pAML (N=202; TCGA), and other publicly available data for a total of 333 exomes; 10 patients were studied serially. Paired DNA (marrow/CD3+ cells) was subjected to WES, sequence-aligned by BW Aligner, and variants detected via GATK pipeline (Broad Institute). We used defined criteria to minimize false-positives: P5% prevalence, and not found in ex/internal SNP databases. This narrowed the spectrum to 645 mutations (54 genes) for analysis with clinical/phenotypic correlations. Mutations were isolated or grouped by pathway, e.g., PRC2, cohesin complex, plexins and dyneins, etc. In MDS, examples of prevalent mutations include SF3B1 (14%), DNMT3A (11%) and U2AF1/2 (9%). In MDS/MPN: TET2 (36%), SRSF2 (22%) and ASXL1 (19%) and SETBP1 (6%); in sAML: NRAS/RAS (16%), RUNX1 (16%) and cohesin mutations (12%), in contrast to pAML with mutational spectrum dominated by FLT3, DNMT3A, NMP1 or SMC3/1A (cohesin complex). The exome panel did not cover 20% patients, suggesting that their pathogenesis may be related to less recurrent events (613 candidates: 2nd screening phase). When mutational spectrum of sAML vs pAML were compared, mutants of SF3B1 (7 vs 1%, P=.04), BCOR (7 vs 1%, P=.04), CDH11/23 (13 vs. 1%, P=.003), FMN2 (7 vs. 1%, P=.04), PPFIA2 (7% vs 0%, P=.01), SPTAN1 (7% vs 0%, P=.01) and VPS8 (7 vs 0%, P=.017) were more frequent in sAML while DNMT3A and NPM1 were less common. Analysis of MDS/MPN revealed mutations in PRC2 (2 vs 11%, P=.05), SRSF2 (5 vs. 22%, P=.010) and TET2 (3 vs. 33%, P<.001) more frequent than in MDS. Mutations in SF3B1 were more recurrent in low/Int-1 IPSS categories compared to Int-2/high/sAML (21 vs. 3%, P=.01), in which mutations in N/KRAS (0 vs. 14%, P=.01) and TP53 (0 vs. 14%, P=.01) were more frequent. Functional group comparisons revealed that lesions in epigenetic (56 vs 23%, P=.001) and signal transduction genes (36 vs 9%, P=.001) were more prevalent in MDS/MPN compared to MDS in which they accumulated according to risk (high vs low: 36 vs 5%, P=.001 or 52% in pAML). Spliceosomal mutations were overrepresented in MDS/MPN vs MDS (58 vs 37%, P=.031), in sAML vs pAML (23 vs 9%, P=.032), and in low risk vs high risk cases (45 vs 22%, P=.02). Cytoskeleton organization gene mutations were overrepresented in sAML vs pAML (39 vs 13%, P=.001). TSG were more frequent in high-risk vs low-risk MDS (30 vs 5%, P=.003). Moreover, TET2 mutations coincided with SRSF2 and PRC2 mutations (P<.001 and P=.010); DNMT3 mutations with SF3B1 and BCOR (P=.04 and P=.004); SRSF2 with ASXL1 (P=.017); RUNX1 with cohesin and BCOR (P=.003 and P=.04), CBL mutations with PRPF8 and ASXL1 (P=.04 or P=.003); TP53 with PRPF8 (P=.04).
After analyzing survival impact of individual mutations, functional groups, cytogenetic category and clinical parameters, we found TP53, ETV6, PRPF8, FMN2, UMODL1, KIT, GATA2, complex karyotype and chr. 5 anomalies had a prognostic impact on OS. However, in multivariate analyses, the first variable to stratify our cohort was, as expected, the diagnosis subtype (HR 2.2, P<.001), but also mutations in PRPF8 (HR 5.4, P=.004). In MDS and grouped MDS/MPN, significant variables included KIT (HR 12, P=.022) and TP53 mutations (HR 3.6, P=.045). Apart from traditional analyses, we also applied a recursive partitioning algorithm to construct an unbiased survival tree encompassing every mutation: e.g., PRPF8, CSMD1, U2AF2, IDH2, PPFIA2, SF3B1 and NRAS showed the highest difference in OS with this method.
In sum, mutational spectrum of myeloid neoplasms can be assessed with WES. The pattern of frequency and concurrence in each diagnostic subtype differs substantially, a feature that can be exploited diagnostically. Despite heterogeneity, mutations and their combinations can be found to categorize patients and serve as prognostic markers. Analysis of additional cases is ongoing and will be presented at the meeting.
Disclosures:
Makishima: Scott Hamilton CARES Initiative: Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding
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Clinical “MUTATOME” Of Myelodysplastic Syndrome; Comparison To Primary Acute Myelogenous Leukemia
Abstract
Chromosomal aberrations and somatic mutations constitute key elements of the pathogenesis of myelodysplastic syndromes (MDS), a clonal hematologic malignancy characterized by cytopenias, a dysplastic bone marrow and propensity to clonal evolution. Next generation sequencing (NGS) enables definition of somatic mutational patterns and clonal architecture as a discovery platform, and for clinical applications.
We systematically applied NGS to 707 cases of MDS and MDS-related disorders. 205 cases (low-risk MDS: N=78, high-risk MDS: N=42, MDS/MPN: N=48 and sAML: N=37) were tested by whole exome sequencing (WES). For validation in an additional 502 patients (low-risk MDS: N=192, high-risk MDS: N=104, MDS/MPN: N=111 and sAML: N=95), targeted deep NGS was applied for 60 index genes which were most commonly affected in the cohort analyzed by WES. For NGS data analysis a statistical pipeline was developed to focus on: i) identification of the most relevant somatic mutations, and ii) minimization of false positive results. We studied serial samples from 21 exemplary informative patients. We also compared somatic mutational patterns to those seen in primary AML TCGA cohort (N=201). Given the size of the cohort, there was, for example, a 87% chance of seeing mutations at a frequency of 1% and a 98% of seeing those with a frequency of 2%. While focusing on the most common events, we observed 1117 somatic mutations in 199 genes. The 88 genes mutated mutated in >1% of cases with MDS carried 388 mutations in MDS+sAML (2.5/case), 128 in MDS/MPN (2.7/case) and 398 in pAML (2.0/case). The average number of mutations per case increased during progression (2.2 in lower-risk, 2.8 in higher-risk MDS, 3.4 in sAML). In MDS, the 30 most frequently affected genes were present at least once in 70% of patients. The 30 most frequently mutated genes in MDS/MPN were mutated in 82% of patients. Individual mutations were also sub-grouped according to their function. When we compared three MDS subcategories (lower-risk, higher-risk MDS and sAML) in a cross-sectional view, RTK family, RAS family, IDH family and cohesin family mutations were more frequently detected in the sAML group than in the MDS group. In contrast, the frequency of the DNMT family, TET2 and ASXL family gene mutations did not increase in frequency in the sAML cohort. In addition to better definition of mutational patterns of known genes, we have also defined new mutations, including in the RNA helicase family and the BRCC3pathway.
Clonal architecture analysis indicates that mutations of TET2, DNMT3A, ASXL1, and U2AF1 most likely represent ancestral/originator events, while those of the IDH family, RTK family and cohesin family are typical secondary events. Establishment of mutational patterns may improve the precision of morphologically-based diagnosis. The comparison between MDS-related diseases (MDS+sAML) and pAML revealed a notably different mutational pattern suggestive of a distinct molecular derivation of these two disease groups. While RTK, IDH family and NPM1 mutations were more frequently observed in the pAML cohort, mutations of SF3B1 and SRSF2, were more common in MDS+sAML. With regard to the connections between individual mutation combinations, RTK mutations were strongly associated with DNMT, but not with RAS family mutations in the pAML cohort, while the mutual association between TET2 and PRC2 family, cohesin family and RUNX1were encountered in the MDS+sAML cohort.
Individual mutations may have prognostic significance, including having an impact on survival, either within the entire cohort or within specific subgroups. In the combined MDS cohort, TP53 family mutations were associated with a poor prognosis (HR; 3.65, 95%CI; 1.90-7.01, P<.0001) by univariate analysis. Similar results were found for mutations in TCF4(HR; 7.98, 95%CI; 1.58-10.1, P<.0007). Such an individual approach does not allow for assessment of the impact of less common mutational events.
In conclusion, our study continues to indicate the power of NGS in the molecular analysis of MDS. MDS and related disorders show a great deal of pathogenetic molecular overlap, consistent with their morphologic and clinical pictures, but also distinct molecular differences in mutational patterns. Some of the specific mutations are pathognomonic for specific subtypes while some may convey a prognostic rather than discriminatory value.
Disclosures:
Makishima: Scott Hamilton CARES grant: Research Funding; AA & MDS international foundation: Research Funding. Polprasert:MDS foundation: Research Funding
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Serial Sequencing in Myelodysplastic Syndromes Reveals Dynamic Changes in Clonal Architecture and Allows for a New Prognostic Assessment of Mutations Detected in Cross-Sectional Testing
Abstract
MDS and related disorders, including MDS/MPN and sAML that evolved from these conditions constitute disease continuum characterized by a wide spectrum of molecular lesions which often overlap. Here, we defined general mutational spectrum and clonal architecture in a large cohort (n=718) of MDS studied by whole exome sequencing (WES) and target deep sequencing. Within this cohort 97 cases were studied at multiple time points to clarify the clinical impact of clonal dynamics on phenotype commitment or outcomes. All samples were obtained after informed consent, according to protocols approved by the respective ethics boards of the participating institutions.
When mean and maximum variant allele frequency (VAF) for whole mutations were at one time-point evaluated in disease phenotypes, significantly higher averaged values suggested their larger clones in sAML and CMML compared to MDS. Clustering analysis of multiple mutational events by Pyclone software discriminated the cases with multiple mutational clones (positive heterogeneity) and those with a single expansion of MDS clone (no heterogeneity detected). Over 80% of low-risk MDS and all the sAML harbored multiple clusters of mutations. These results suggest that intra-tumor heterogeneity of MDS is most likely due to various sizes of clonal and subclonal mutations, likely impacting clinical behavior.
To delineate clonal dynamics in MDS, we assessed mutational burden and their temporal changes in serially collected samples (n=97). Among these, Pyclone analysis was applied to exome sequencing at two time points (n=11 pairs). All cases showed various mutational clusters with individual expansions and declines, including initially present, newly acquired or disappearing during clinical course. Initial subclones were identified at disease presentation in 55% of cases, of which in 86% the subclones expanded to occupy whole MDS population with clonal sweep. New subclones acquired during clinical course were identified in 91%, in which 60% cases harbored clonal sweep. Disappearing clones were observed in 55% of cases. Next, we applied clustering analysis on clonal size of driver mutations evaluated at multiple time points (n=97 cases) to categorize the most frequently mutated genes into 3 subtypes. Mutational burden of PTPN11 most frequently increased and were associated with leukemic evolution (an example of type I gene). Similarly, CBL, NRAS, STAG2, RUNX1, and IDH1 were categorized into the type I genes, demonstrating increased clonal size resulting in the evolutions into high-risk phenotypes. Although JAK2 mutations were related to the stable clinical course when the mutational burden decreased, cases with highly expanded JAK2 mutations resulted in leukemic evolution (occasional evolution or expansions; type II gene). DNMT3A, SRSF2, TP53, U2AF1, and ASXL1 mutations were also categorized into such type II consequences with occasional progression. The last category (type III) included clonal/founder genes EZH2, TET2, SF3B1 and PRPF8, demonstrating random shifts of clonal size and lack of association with leukemic evolution.
The proposed hierarchical categorization correlates with clinical parameters. Cases with the increasing burden of type I gene mutations showed most significant increases in myeloblasts. Overall survival measured from second sampling time points in the cases with increasing type I mutations was significantly shorter in the whole cohort (HR=2.05, 95%CI; 1.14-3.79, P=0.016) and in the cases solely with IPSS INT-1 (HR=2.37, 95%CI; 1.01-5.97, P=0.048). Subcohorts classified according to the presence or absence of increasing type I mutations did not differ with regard to the IPSS categories. In contrast, increased mutational burden of type II and III genes did not correlated with any of the clinical parameters examined, even though some gene mutations including TP53, EZH2, and U2AF1 represented poor prognostic factors at disease presentation.
In conclusion, this work demonstrates that detailed understanding of clonal dynamics allows for new insights into clinical significance of somatic mutations, made possible only by serial sample sequencing at multiple time points. Increasing clonal burden of extracted genes associated with predictive prognostic impact should be prospectively validated in more uniform and larger cohort of MDS.
Disclosures
Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Shih:Novartis: Research Funding
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In Analogy to AML, MDS Can be Sub-Classified By Ancestral Mutations
Abstract
Somatic mutations constitute key pathogenetic elements in MDS. Unbiased whole exome sequencing (WES) and deep NGS led to discovery of new somatic mutations and also to the recognition of i) tremendous diversity of mutations and their combinations; ii) individual intra-tumor heterogeneity and clonal hierarchy. Chromosomal lesions further increase the complexity of molecular defects.
While in MDS molecular defects are acquired in order, observations made in AML highlight the importance of ancestral events; e.g., t(8;21), inv16 or t(15;17) and other lesions that are used as the basis for nosological sub-classification. Thus, it is the identity of individual ancestral events or their classes rather than the spectrum of secondary events or the distribution of mutations, that will allow for molecular, functionally-relevant and diagnostically useful classification within MDS. This would explain why only a few somatic mutations have been found to be prognostically important, as their position in the clonal hierarchy has not been accounted for. With this in mind, we applied WES (N=206) and targeted deep NGS (N=836) and studied 100 samples serially with analyses focused on ancestral events.
Globally, through WES we identified and validated 2386 mutational events in 1458 genes. Of these, 112 genes were mutated at significant frequencies (q<0.05); groups of affected genes involved in splicing, transcription, DNA methylation, histone modification, and others were distinguished. On average, 9 somatic events per MDS case, 10.7 in secondary AML, and 12.5 in MDS/MPN were found. Resequencing in combination with SNP-array karyotyping provided information on variant allelic frequency (VAF) adjusted for corresponding zygosity of mutations; 99% of cases displayed clear intra-tumor heterogeneity due to multiple clones defined by hierarchically acquired somatic mutational patterns.
Using cross-sectional analyses, the highest mean VAF could be interpreted as consistent with the ancestral nature of the mutations, as seen for instance in a proportion of TET2 and SF3B1 mutant cases. In contrast, the lowest mean VAF indicated secondary events, as occur in NPM1 and RAS pathway mutations. Similar conclusions were made based on cross-sectional analyses showing a similar distribution of ancestral but not secondary events in MDS and sAML. All gene mutations were categorized into those that are predominantly ancestral and those that are facultatively secondary. The most frequent founder mutations were identified (TET2, DNMT3A, SF3B1, ASXL1, TP53, U2AF1, RUNX1, SRSF2) and used to sub-classify approximately 80% of patients, with the remainder containing more infrequent ancestral mutations. While in a combined fashion (as both founder and secondary events) many of these mutations were not predictive of prognosis, they gained relevance when only cases affected by ancestral mutations were used for prognostication. Thus some of the mutations, when present as secondary events may not be predictive.
Founding mutations may determine subsequent clinical and molecular features. While other frequently affected genes, SF3B1 or ASXL1, are not associated with a significant increase in the number of concomitant mutations, cases with TET2 mutations showed significantly more frequent mutations per case than those with wild-type TET2 (14.6 vs. 9.1; p=0.001). Moreover, ancestral TET2 mutations were associated with concomitant mutations due to high C-to-T transitions, possibly because reduced 5-hydroxymethylcytosine might create the specific mutator milieu.
Most important is the association not of any type, but of ancestral mutations with certain pathomorphologic features and outcomes. Founding TET2 mutations are associated with MPN/MDS while secondary TET2 mutations are present in MDS. Ancestral DNMT3A mutations determine a rapid progression to AML, whereas subclonal DNMT3A mutations are also found in high-risk MDS. RAS pathway mutations are ancestral in CMML and also secondarily positive in the late stage of MDS (sAML). Specific ancestral events may determine subsequent mutational events, and while both types of mutation may affect the clinical phenotype, the initial events are less diverse and more subtype-specific. In conclusion, WES clarified the distinct landscape and ordering of the somatic mutational spectrum in MDS.
Disclosures
No relevant conflicts of interest to declare
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the Impact of Clonal Dynamics on Prognosis and Outcome in Myelodysplastic Syndromes
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic myeloid neoplasms, in which disease progression is quite common, eventually terminating in secondary acute myeloid leukemia (sAML). To elucidate differential roles of mutations in MDS progression and sAML evolution, we investigated clonal dynamics of somatic mutations using targeted sequencing of 699 MDS patients, of which 122 were analyzed for longitudinally collected samples. Combining publicly available data, mutational data in a total of 2,250 MDS cases were assessed for their enrichment in specific disease subtypes. All samples were obtained after informed consent.
Genotyping data from samples with low- (n=1,207) and high-risk (n=683) MDS as well as sAML (n=360) were available for most prevalently mutated 25 driver genes. In univariate comparison between low- and high-risk MDS, the majority of differentially mutated genes were enriched in high-risk MDS, except for SF3B1, which was more frequently mutated in low-risk MDS. Multivariate analysis was performed using a least absolute shrinkage and selection operator model. As a result, mutations in 7 genes (FLT3, PTPN11, WT1, IDH1, NPM1, IDH2,and NRAS) designated as 'Type-1' mutations, were significantly enriched in sAML compared to high-risk MDS. When comparison was made between high- and low-risk MDS, mutations in 10 genes, including GATA2, NRAS, KRAS, IDH2, TP53, RUNX1, STAG2, ASXL1, ZRSR2, and TET2, were enriched in high-risk MDS. The latter mutations are designated as 'Type-2' mutations, excluding NRAS and IDH2 mutations, which were already assigned to the Type-1 category.
To characterize the chronological behavior of Type-1 and Type-2 mutations, we performed longitudinal analyses of 122 cases, of which 90 progressed to sAML. Overall, driver mutations tended to increase their clone sizes between two time points. In accordance with their significant enrichment in sAML, Type-1 mutations were more likely to be newly acquired at the second time points, compared to Type-2 and other mutations (P=0.0001). By contrast, in patients with high-risk MDS at the second time point, Type-2 mutations were more dominant than Type-1 mutations, and most of the Type-2 mutations (88%) increased their clone sizes at the second sampling. Similarly, Type-2 mutations found in high-risk MDS or sAML evolving from low-risk MDS increased their clone sizes more frequently (30 out of 38 mutations (79%)) than Type-2 mutations in stable low-risk MDS without disease progression over time (4 out of 11 (36%)) (P=0.02). These findings suggest that Type-1 and Type-2 mutations might be associated with progression from high-risk MDS to sAML and low- to high-risk MDS, respectively.
To further clarify the effects of the different classes of mutations on progression to sAML, 429 patients with MDS were analyzed for progression free survival (or PFS). Patients with Type-1 mutations (Group-I) had a significantly shorter PFS, compared to those who had Type-2 mutations but lacked Type-1 mutations (Group-II) (HR=1.82, 95% CI:1.08−3.05; P=0.025). Nevertheless, PFS in Group-II cases was still significantly shorter than that in other cases (HR=2.46, 95% CI:1.43−4.23; P=0.001). Of note, some Group-II cases subsequently acquired Type-I mutations during progression to sAML. By contrast, SF3B1-mutated patients tended to show slower progression to sAML, unless they carried either of Type-1 or 2 mutations (Group-III). Finally, the effects of these mutations on overall survival (OS) were assessed in a larger cohort of patients with MDS (n=1,347). Group-I cases were shown to have a significantly shorter OS than Group-II cases (HR=1.50, 95% CI:1.20−1.86; P<0.001). Other independent prognostic factors included the International Prognostic Scoring System (IPSS) score and the mutational category (i.e., Group-I, -II, and -III) for PFS, while the presence of complex karyotypes, together with IPSS score, Group-I, -7/del(7q), age, and del(20q) were among the negative predictors of OS.
In conclusion, our study has elucidated clonal dynamics associated with MDS progression and sAML evolution. Close monitoring of these sets of distinct mutations in the prospective fashion may help in the prediction of the clinical outcome in MDS.
Disclosures
Makishima: The Yasuda Medical Foundation: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Ogawa:Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding
Dynamics of clonal evolution in myelodysplastic syndromes
To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring