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1.
J Clin Oncol ; : JCO1900640, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509472

RESUMO

PURPOSE: To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics. PATIENTS AND METHODS: The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS). RESULTS: In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 109/L), presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; P < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival (P < .001). CONCLUSION: The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.

3.
PLoS Comput Biol ; 15(8): e1007332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31469830

RESUMO

The confluence of deep sequencing and powerful machine learning is providing an unprecedented peek at the darkest of the dark genomic matter, the non-coding genomic regions lacking any functional annotation. While deep sequencing uncovers rare tumor variants, the heterogeneity of the disease confounds the best of machine learning (ML) algorithms. Here we set out to answer if the dark-matter of the genome encompass signals that can distinguish the fine subtypes of disease that are otherwise genomically indistinguishable. We introduce a novel stochastic regularization, ReVeaL, that empowers ML to discriminate subtle cancer subtypes even from the same 'cell of origin'. Analogous to heritability, implicitly defined on whole genome, we use predictability (F1 score) definable on portions of the genome. In an effort to distinguish cancer subtypes using dark-matter DNA, we applied ReVeaL to a new WGS dataset from 727 patient samples with seven forms of hematological cancers and assessed the predictivity over several genomic regions including genic, non-dark, non-coding, non-genic, and dark. ReVeaL enabled improved discrimination of cancer subtypes for all segments of the genome. The non-genic, non-coding and dark-matter had the highest F1 scores, with dark-matter having the highest level of predictability. Based on ReVeaL's predictability of different genomic regions, dark-matter contains enough signal to significantly discriminate fine subtypes of disease. Hence, the agglomeration of rare variants, even in the hitherto unannotated and ill-understood regions of the genome, may play a substantial role in the disease etiology and deserve much more attention.

6.
Blood ; 134(2): 199-210, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31064751

RESUMO

Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3' splicing patterns, many of these with a protein-altering potential. Finally, from all mutations detected, we generated a virtual peptide library and used NetMHC to predict 149 unique neoantigens in 62% of MPN patients. Peptides from CALR and MPL mutations provide a rich source of neoantigens as a result of their unique ability to bind many common MHC class I molecules. Finally, we propose that mutations derived from splicing defects present in SF3B1-mutated patients may offer an unexplored neoantigen repertoire in MPNs. We validated 35 predicted peptides to be strong MHC class I binders through direct binding of predicted peptides to MHC proteins in vitro. Our results may serve as a resource for personalized vaccine or adoptive cell-based therapy development.

8.
Genes Chromosomes Cancer ; 58(10): 698-704, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994218

RESUMO

Deletions in the long arm of chromosome 7 (del(7q)) are recurrent cytogenetic aberrations in myeloid neoplasms. They occur either isolated or as part of a complex karyotype and are associated with unfavorable prognosis in certain disease entities. We performed detailed cytogenetic analysis, molecular analysis, and array comparative genomic hybridization in a cohort of 81 patients with a variety of myeloid malignancies and del(7q) as sole chromosomal alteration. In 70% (57/81) of patients, we identified a commonly deleted region (size: 18 Mb) involving the genomic region 101 912.442 (7q22.1)-119 608.824 (7q31.31). Furthermore, in 80 patients, we analyzed 17 genes commonly mutated in myeloid neoplasms and identified high mutation frequencies in ASXL1 34% (27/80), TET2 33% (26/80), RUNX1 25% (20/80), DNMT3A 25% (20/80), while TP53 was rarely affected (5%, 4/80). ASXL1 and TET2 showed similar mutation frequencies across all analyzed entities while RUNX1, CBL, and JAK2 were specifically mutated in patients with acute myeloid leukemia (AML), chronic myelomonocytic leukemia, and myeloproliferative neoplasms, respectively. We detected a significantly higher frequency of RUNX1 (42% vs 13%, P = .0001) and ASXL1 (32% vs 14%, P = .008) mutations in AML patients with del(7q) compared to other AML patients in the Medical Research Council unfavorable risk group (n = 464), indicating a cooperative leukemogenic potential. Our data provide further insight into the pathomechanism of this cytogenetic subgroup.

9.
Nat Genet ; 51(4): 694-704, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926971

RESUMO

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.


Assuntos
Leucemia Eritroblástica Aguda/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genômica/métodos , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Prognóstico , Proteína Supressora de Tumor p53/genética , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
12.
Blood ; 133(10): 1006-1007, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846508
14.
Leukemia ; 33(5): 1124-1134, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30635631

RESUMO

KIT D816 mutations (KIT D816mut) are strongly associated with systemic mastocytosis (SM) but are also detectable in acute myeloid leukemia (AML), where they represent an adverse prognostic factor in combination with core binding factor (CBF) fusion genes. Here, we evaluated the clinical and molecular features of KIT D816mut/CBF-negative (CBFneg) AML, a previously uncharacterized combination. All KIT D816mut/CBFneg cases (n = 40) had histologically proven SM with associated AML (SM-AML). Molecular analyses revealed at least one additional somatic mutation (median, n = 3) beside KIT D816 (e.g., SRSF2, 38%; ASXL1, 31%; RUNX1, 34%) in 32/32 (100%) patients. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm. Longitudinal molecular and cytogenetic analyses revealed the acquisition of new mutations and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Median overall survival (OS) was 5.4 months. A screen of two independent AML databases (AMLdatabases) revealed remarkable similarities between KIT D816mut/CBFneg SM-AML and KIT D816mut/CBFneg AMLdatabases (n = 69) with regard to KIT D816mut variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AMLdatabases patients. Bone marrow histology and reclassification as SM-AML has important clinical implications regarding prognosis and potential inclusion of KIT inhibitors in treatment concepts.


Assuntos
Alelos , Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Medula Óssea/patologia , Análise Citogenética , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/metabolismo , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade
18.
Blood Adv ; 2(22): 3118-3125, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30455361

RESUMO

Acute myeloid leukemia (AML) with NPM1 mutation (NPM1 mut) defines a World Health Organization entity. Absence of minimal residual disease (MRD) following induction chemotherapy is associated with an excellent prognosis. Data are conflicting on NPM1 mut AML relapsing with wild-type NPM1 (NPM1 wt ). We analyzed 104 paired samples of NPM1 mut AML patients with relapse and identified 14/104 that relapsed with NPM1 wt AML. Blood counts at diagnosis differed significantly between patients with NPM1 mut and NPM1 wt relapse (median white blood cell count, 30 vs 3 × 109/L, P = .008; platelet count, 66 vs 128 × 109/l, P = .018). NPM1 mut relapse occurred significantly earlier than NPM1 wt relapse (14 vs 43 months, P = .004). At diagnosis, FLT3-ITD were more frequent in patients with NPM1 mut relapse (P = .029), whereas DNMT3A mutations were more frequent in patients with NPM1 wt relapse (P = .035). Sequencing analysis of paired samples at diagnosis, molecular remission, and NPM1 wt relapse identified cooccurring mutations that persist from diagnosis throughout remission and at relapse, suggestive of a preexisting clonal hematopoiesis. We provide evidence that AML relapsing with NPM1 wt is a distinct disease and that initial leukemia and relapse potentially arise from a premalignant clonal hematopoiesis.

19.
Haematologica ; 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093396

RESUMO

Chromosomal translocation t(8;21)(q22;q22) which leads to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting not only myeloid and erythroid differentiation but also maturation of lymphoid cells. Overall, these findings establish a critical role of ASXL2 in maintaining steady state hematopoiesis and provide insights into how its loss primes expansion of myeloid cells.

20.
Br J Haematol ; 183(1): 47-59, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30022491

RESUMO

Chronic Lymphocytic Leukaemia (CLL) is a heterogeneous disease with a clinical course dependent on cytogenetic features. However, in 15-20% of cases both chromosome banding and fluorescence in situ hybridisation analyses do not show any kind of abnormality. With the aim to identify dependable molecular prognostic factors in this subgroup, we performed a comprehensive analysis on 171 patients including genomic arrays (comparative genomic hybridisation and single nucleotide polymorphism), immunoglobulin heavy chain variable region genes (IGHV) status, flow cytometry and targeted sequencing. Genomic arrays detected 73 aberrations in 39 patients (23%). Most frequently, patients had 1 aberration (25/171; 15%), while 14 patients (8%) had at least 2 aberrations. IGHV status was unmutated in 53/171 (31%) patients. SF3B1 was the most frequently mutated gene (26/171 patients; 15%), followed by NOTCH1 (15/171; 9%). At univariate analysis, an adverse impact on time to treatment (TTT) was evident for SF3B1 mutations, higher white blood cell count, higher CLL cells percentage by flow cytometry, CD38 positivity, IGHV unmutated status and at least 2 genomic array abnormalities. Of these, SF3B1 mutations, CLL cells percentage, IGHV unmutated status and number of genomic array aberrations maintained their impact in multivariate analysis. In conclusion, by integrating genomic and molecular data, we identified patients at higher risk for treatment need.

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