RESUMEN
Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Colitis Ulcerosa/genética , Tasa de Mutación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular Tumoral , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Neoplasias Colorrectales/genética , Humanos , Ratones , Transducción de SeñalRESUMEN
Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently for lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germ line DDX41 variants include truncating alleles that comprise about two-thirds of all alleles, missense variants located preferentially within the DEAD-box domain, and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germ line genetic testing because >95% of such alleles are germ line. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germ line DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germ line DDX41 alleles are noteworthy: (1) certain variants are common in particular populations, (2) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people, (3) despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis, and (4) individuals with deleterious germ line DDX41 variants develop acute severe graft-versus-host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive posttransplant cyclophosphamide, suggesting a proinflammatory milieu that stimulates donor-derived T cells. Biochemical studies and animal models have identified DDX41's ability to interact with double-stranded DNA and RNA:DNA hybrids with roles in messenger RNA splicing, ribosomal RNAs or small nucleolar RNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.
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ARN Helicasas DEAD-box , Leucemia Mieloide , Trastornos Mieloproliferativos , Animales , Femenino , ARN Helicasas DEAD-box/genética , Mutación de Línea Germinal , Trastornos Mieloproliferativos/genética , ARN Mensajero , Humanos , MasculinoRESUMEN
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained â¼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
Asunto(s)
ARN Helicasas DEAD-box , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Masculino , ARN Helicasas DEAD-box/genética , Células Germinativas , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genéticaRESUMEN
Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.
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Envejecimiento/genética , Envejecimiento/patología , Epitelio , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Mutación , Lesiones Precancerosas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/genética , Biopsia , Recuento de Células , Transformación Celular Neoplásica/genética , Niño , Preescolar , Células Clonales/metabolismo , Células Clonales/patología , Variaciones en el Número de Copia de ADN , Epitelio/metabolismo , Epitelio/patología , Evolución Molecular , Femenino , Interacción Gen-Ambiente , Genoma Humano/genética , Humanos , Lactante , Estilo de Vida , Masculino , Persona de Mediana Edad , Acumulación de Mutaciones , Proteína Fosfatasa 2C/genética , Receptor Notch1/genética , Factores de Riesgo , Análisis de Secuencia de ADN , Análisis de la Célula Individual , Fumar/genética , Adulto JovenRESUMEN
Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole-genome (WGS), whole-exome (WES) and/or targeted-sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness-associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17, FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2-fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.
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Fibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Variaciones en el Número de Copia de ADN , Exoma , Fibrosarcoma/genética , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Secuenciación del ExomaRESUMEN
Morphologic interpretation is the standard in diagnosing myelodysplastic syndrome (MDS), but it has limitations, such as varying reliability in pathologic evaluation and lack of integration with genetic data. Somatic events shape morphologic features, but the complexity of morphologic and genetic changes makes clear associations challenging. This article interrogates novel clinical subtypes of MDS using a machine-learning technique devised to identify patterns of cooccurrence among morphologic features and genomic events. We sequenced 1079 MDS patients and analyzed bone marrow morphologic alterations and other clinical features. A total of 1929 somatic mutations were identified. Five distinct morphologic profiles with unique clinical characteristics were defined. Seventy-seven percent of higher-risk patients clustered in profile 1. All lower-risk (LR) patients clustered into the remaining 4 profiles: profile 2 was characterized by pancytopenia, profile 3 by monocytosis, profile 4 by elevated megakaryocytes, and profile 5 by erythroid dysplasia. These profiles could also separate patients with different prognoses. LR MDS patients were classified into 8 genetic signatures (eg, signature A had TET2 mutations, signature B had both TET2 and SRSF2 mutations, and signature G had SF3B1 mutations), demonstrating association with specific morphologic profiles. Six morphologic profiles/genetic signature associations were confirmed in a separate analysis of an independent cohort. Our study demonstrates that nonrandom or even pathognomonic relationships between morphology and genotype to define clinical features can be identified. This is the first comprehensive implementation of machine-learning algorithms to elucidate potential intrinsic interdependencies among genetic lesions, morphologies, and clinical prognostic in attributes of MDS.
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Aprendizaje Automático , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Similar with myelodysplastic syndromes (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are the major bone marrow failure syndromes. Approximately 10-20% of patients with AA/PNH present with transformation into MDS. Clonal hematopoiesis in AA/PNH affected by karyotypic abnormalities and genetic mutations should be discriminated from MDS clone, which is sometimes difficult due to shared genetic events among these diseases. In patients with AA/PNH, clones with UPD6p and PIGA mutations are selected under autoimmune pressure, and those with DNMT3A, ASXL1, and TET2 mutations originated from clonal hematopoiesis of indeterminate potential (CHIP) frequently identified in elderly healthy individuals. In patients with cytopenia, a single CHIP mutation is insufficient for MDS presentation. However, TP53 and U2AF1 mutations, which are not in the list of typical CHIP mutations, are observed in patients with AA with future MDS transformation. Therefore, clonal hematopoiesis in AA/PNH, partially overlapping the MDS clone, is caused by autoimmunity and originates from CHIP, demonstrating distinct genetic profiles.
Asunto(s)
Anemia Aplásica , Hemoglobinuria Paroxística , Síndromes Mielodisplásicos , Anciano , Anemia Aplásica/genética , Hematopoyesis Clonal , Hematopoyesis/genética , Hemoglobinuria Paroxística/genética , Humanos , Síndromes Mielodisplásicos/genética , Factor de Empalme U2AF/genéticaRESUMEN
Recent advances in sequencing technologies have increased the detection rate for identifying germline mutations that predispose an individual to various myeloid neoplasms and somatic mutations acquired during progression from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML). In addition to pediatric subjects, adult patients were analyzed in order to obtain a complete spectrum of driver mutations in germline cells and/or somatic tumor samples. As shown in several recent studies, such driver mutations are acquired in a gene-specific fashion. DDX41 mutations are observed in germline cells long before MDS presentation. SAMD9/SAMD9L germline mutations associated with defective hematopoiesis account for recurrent and familial -7/del (7q) lesions, which result in the removal of the disadvantageous allele. Additionally, MDS cases in younger population display compound heterozygous germline mutations in the Shwachman-Diamond syndrome-associated SBDS gene. In peripheral blood samples from healthy elderly individuals, DNMT3A, TET2, and ASXL1 somatic mutations are usually detected due to age-related clonal hematopoiesis and are considered to be a risk factor for hematological neoplasms. In MDS, mutations of genes, such as NRAS and FLT3, designated as type-1 genes, are significantly associated with leukemic evolution. On the other hand, mutations in type-2 genes, including RUNX1 and GATA2, are related to progression from low risk MDS to high risk MDS.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Adulto , Anciano , Niño , Mutación de Línea Germinal , Humanos , Péptidos y Proteínas de Señalización Intracelular , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genéticaRESUMEN
Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chromosomes 3, 8, and 11. However, there was no difference in the median survival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure.
Asunto(s)
Supervivientes a la Bomba Atómica , Síndromes Mielodisplásicos , Aberraciones Cromosómicas , Humanos , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/genética , Factores de Riesgo , SobrevivientesRESUMEN
Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic disorders with a highly variable prognosis. To identify a gene expression-based classification of myelodysplasia with biological and clinical relevance, we performed a comprehensive transcriptomic analysis of myeloid neoplasms with dysplasia using transcriptome sequencing. Unsupervised clustering of gene expression data of bone marrow CD34+ cells from 100 patients identified 2 subgroups. The first subtype was characterized by increased expression of genes related to erythroid/megakaryocytic (EMK) lineages, whereas the second subtype showed upregulation of genes related to immature progenitor (IMP) cells. Compared with the first so-called EMK subtype, the IMP subtype showed upregulation of many signaling pathways and downregulation of several pathways related to metabolism and DNA repair. The IMP subgroup was associated with a significantly shorter survival in both univariate (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.8-14; P = .002) and multivariate analysis (HR, 4.9; 95% CI, 1.3-19; P = .02). Leukemic transformation was limited to the IMP subgroup. The prognostic significance of our classification was validated in an independent cohort of 183 patients. We also constructed a model to predict the subgroups using gene expression profiles of unfractionated bone marrow mononuclear cells (BMMNCs). The model successfully predicted clinical outcomes in a test set of 114 patients with BMMNC samples. The addition of our classification to the clinical model improved prediction of patient outcomes. These results indicated biological and clinical relevance of our gene expression-based classification, which will improve risk prediction and treatment stratification of MDS.
Asunto(s)
Transformación Celular Neoplásica/genética , Perfilación de la Expresión Génica/métodos , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/metabolismo , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.
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Aberraciones Cromosómicas , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genética , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Riesgo , Trasplante Homólogo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/metabolismo , Proteínas ras/metabolismoRESUMEN
Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous myeloid neoplasms that frequently evolve into secondary acute myeloid leukemia (sAML). Recent progress in next-generation sequencing technologies has allowed us to discover frequent mutations throughout the coding regions of MDS, MDS/MPN, and sAML, subsequently providing information on more than 60 driver genes in these diseases. As shown by many study groups recently, such driver mutations are acquired in a gene-specific fashion. DDX41 and SAMD9/SAMD9L mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A, TET2, and ASXL1 mutations are detected as age-related clonal hematopoiesis and supposed to be a risk factor for hematological neoplasms. Recent reports on MDS have shown that mutations in genes such as NRAS and FLT3, designated as Type I genes, were significantly associated with leukemic evolution. Another type (Type II) of genes, including RUNX1 and GATA2, has been shown to be related to the progression from low-risk to high-risk MDS. These driver mutations are significantly concomitant during disease progression. Overall, various types of driver mutations are sequentially acquired in MDS, accounting for the heterogeneity of these disorders.
Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Genómica , HumanosRESUMEN
BACKGROUND: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. METHODS: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. RESULTS: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. CONCLUSIONS: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).
Asunto(s)
Anemia Aplásica/genética , Hematopoyesis/genética , Mutación , Factores de Edad , Anciano , Anemia Aplásica/sangre , Anemia Aplásica/mortalidad , Células Clonales , Femenino , Humanos , Cariotipificación , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Análisis de Secuencia de ADNRESUMEN
Aplastic anemia (AA) is an autoimmune-mediated bone marrow failure syndrome. While AA is not a malignant disease, clonal hematopoiesis is commonly detected via next-generation sequencing and single nucleotide polymorphism (SNP) array. Clonal hematopoiesis in AA has been confirmed by the detection of classic X chromosome skewing, PNH clones, UPD6p, and various mutations. The most frequent genetic events in AA are UPD6p and somatic mutations in BCOR/BCORL1, PIGA, DNMT3A, and ASXL1. While some mutations are common between patients with AA and healthy elderly donors, UPD6p and PIGA mutations are specific to clonal cells in AA, which need to manage their highly autoimmune extrinsic environment. During the evolution of AA into myelodysplastic syndrome (MDS), additional genetic events are frequently acquired that provide MDS cells with intrinsic survival benefits. Hematopoietic cells in AA appear to achieve clonal expansion by their escape from recognition and cytotoxicity by CD8 T-cells, accounting for the distinct landscape of genetic events observed in AA.
Asunto(s)
Anemia Aplásica/patología , Hematopoyesis , Síndromes Mielodisplásicos/patología , Humanos , Mutación , Polimorfismo de Nucleótido SimpleRESUMEN
Myelodysplastic syndromes are typically diseases of older adults. Patients in whom the onset is early may have distinct molecular and clinical features or reflect a demographic continuum. The identification of differences between "early onset" patients and those diagnosed at a traditional age has the potential to advance understanding of the pathogenesis of myelodysplasia and may lead to formation of distinct morphological subcategories. We studied a cohort of 634 patients with various subcategories of myelodysplastic syndrome and secondary acute myeloid leukemia, stratifying them based on age at presentation and clinical parameters. We then characterized molecular abnormalities detected by next-generation deep sequencing of 60 genes that are commonly mutated in myeloid malignancies. The number of mutations increased linearly with age and on average, patients >50 years of age had more mutations. TET2, SRSF2, and DNMT3A were more commonly mutated in patients >50 years old compared to patients ≤50 years old. In general, patients >50 years of age also had more mutations in spliceosomal, epigenetic modifier, and RAS gene families. Although there are age-related differences in molecular features among patients with myelodysplasia, most notably in the incidence of SRSF2 mutations, our results suggest that patients ≤50 years old belong to a disease continuum with a distinct pattern of early onset ancestral events.
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Edad de Inicio , Mutación , Síndromes Mielodisplásicos/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Factores de Empalme Serina-Arginina/genética , Adulto JovenRESUMEN
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.
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Dihidropiridinas/farmacología , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Pirazoles/farmacología , Regulación Alostérica , Sitio Alostérico , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Islas de CpG , Cristalografía por Rayos X , Citosina/química , Citosina/metabolismo , Metilación de ADN/efectos de los fármacos , Dihidropiridinas/química , Dihidropiridinas/farmacocinética , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Granulocitos/efectos de los fármacos , Granulocitos/enzimología , Granulocitos/patología , Humanos , Isocitrato Deshidrogenasa/química , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Cinética , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Modelos Moleculares , Mutación , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Células Madre Neoplásicas/patología , Cultivo Primario de Células , Unión Proteica , Pirazoles/química , Pirazoles/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Recent progress in next-generation sequencing technologies allows us to discover frequent mutations throughout the coding regions of myelodysplastic syndromes (MDS), potentially providing us with virtually a complete spectrum of driver mutations in this disease. As shown by many study groups these days, such driver mutations are acquired in a gene-specific fashion. For instance, DDX41 mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A and TET2 mutations are detected as age-related clonal hematopoiesis and are believed to be a risk factor for hematological neoplasms. In MDS, mutations of genes such as NRAS and FLT3, designated as Type-1 genes, may be significantly associated with leukemic evolution. Another type (Type-2) of genes, including RUNX1 and GATA2, are related to progression from low-risk to high-risk MDS. Overall, various driver mutations are sequentially acquired in MDS, at a specific time, in either germline cells, normal hematopoietic cells, or clonal MDS cells.
Asunto(s)
Mutación , Síndromes Mielodisplásicos/genética , Envejecimiento , ARN Helicasas DEAD-box/genética , Genoma Humano , Humanos , Síndromes Mielodisplásicos/diagnóstico , PronósticoRESUMEN
Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017).
Asunto(s)
Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Genes Relacionados con las Neoplasias , Leucemia Mieloide Aguda , Mutación , Trastornos Mieloproliferativos , Anciano , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Estudios Transversales , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/mortalidad , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Tasa de Supervivencia , CohesinasRESUMEN
Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations in the spliceosomal genes (U2AF1 and SRSF2) predict for poor outcomes in myelodysplastic syndromes (MDS) and related diseases. We investigated the effect of hematopoietic cell transplant (HCT) on the negative prognostic impact of U2AF1 and SRSF2 mutations. In total, 122 patients with MDS (30%), acute myeloid leukemia (51%), myeloproliferative neoplasms (MPN) (11%), and MDS/MPN (8%) receiving a HCT from 2003 to 2012 were evaluated for mutations in U2AF1 and SRSF2 by direct sequencing. Median time of follow up was 24 months (range 0.46-110). SRSF2 mutations were detected in 11 (10%) patients and U2AF1 in 3 (3%) patients. There were no significant differences in baseline characteristics between mutated and wild-type (WT) patients. Patients carrying SRSF2 and U2AF1 mutations had similar overall survival (P = 0.84), relapse mortality (P = 0.50), and non-relapse mortality (P = 0.72) compared to WT patients. However, taking into account disease status and cytogenetics in a subset of AML patients, SRSF2 and U2AF1 mutations were associated with worse survival (HR 3.71, P = 0.035).
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide/genética , Leucemia Mieloide/terapia , Mutación , Empalmosomas/genética , Exones , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Proteínas Nucleares/genética , Pronóstico , Ribonucleoproteínas/genética , Factores de Empalme Serina-Arginina , Factor de Empalme U2AF , Donantes de Tejidos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Acquired bone marrow failure syndromes consist of aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS). Clonal hematopoiesis is frequently observed in non-neoplastic disorders, aplastic anemia and PNH as well as a neoplastic phenotype, MDS. However, the significance of such clonal hematopoiesis, particularly in aplastic anemia, remains to be elucidated. Recent advancements in next generation sequencing technology have revealed a diverse clonal structure in these bone marrow failure syndromes, as well as in age-related clonal hematopoiesis in healthy people. In this review article, we describe gene mutations in bone marrow failure syndromes, together with those detected in healthy people.