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ABSTRACT: Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs per 1000 patient-years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3%, respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations, or less) and variant allelic frequency of PIGA mutations. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).
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Anticoagulantes , Hemoglobinúria Paroxística , Trombose , Humanos , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Trombose/etiologia , Trombose/tratamento farmacológico , Adulto , Idoso , Anticoagulantes/uso terapêutico , SeguimentosRESUMO
Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.
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Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.
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Leucemia Mieloide Aguda/genética , Aprendizado de Máquina , Teorema de Bayes , Citogenética , Regulação Leucêmica da Expressão Gênica , Genômica , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Mutação , Segunda Neoplasia Primária/classificação , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Translocação GenéticaRESUMO
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR ß and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.
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Anemia Aplástica/genética , Genes MHC da Classe II , Antígenos HLA-D/genética , Adulto , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n=159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n=96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.
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Neoplasias Ósseas , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Biópsia , Medula Óssea/patologia , Curva ROCRESUMO
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Neoplasias Cutâneas , Adulto , Humanos , Células Dendríticas/patologia , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Oncologia , Neoplasias Cutâneas/diagnósticoRESUMO
BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
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Doenças Mieloproliferativas-Mielodisplásicas , Qualidade de Vida , Acetonitrilas , Citidina Desaminase , DNA/uso terapêutico , Decitabina/uso terapêutico , Humanos , Metiltransferases , Estudos Prospectivos , Pirazóis , Pirimidinas , Pirróis , SíndromeRESUMO
Wilms tumor 1 (WT1) gene is commonly mutated in acute myeloid leukemia (AML), particularly in younger age population. The mechanism through which WT1 mutations drive leukemogenesis have not been fully elucidated; however, recent studies reported an association with the epigenetic pathway. Here, we studied the phenotypic characteristics and somatic mutational profile of 114 WT1-mutant AML patients and focused on potential WT1 gene relations to other cooperative genomic events that may impact disease prognosis. Invariant phenotypic and genomic associations of WT1 mutations in AML were uncovered and rigorously described. Our findings help improving the current understanding and definition of WT1-mutant AML patients' characteristics and clinical outcomes.
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Leucemia Mieloide Aguda/genética , Proteínas WT1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Adulto JovemRESUMO
PURPOSE OF REVIEW: The mutational landscape of acute myeloid leukemia (AML) has revised diagnostic, prognostic, and therapeutic schemata over the past decade. Recurrently mutated AML genes have functional consequences beyond typical oncogene-driven growth and loss of tumor suppresser function. RECENT FINDINGS: Large-scale genomic sequencing efforts have mapped the complexity of AML and trials of mutation-based targeted therapy has led to several FDA-approved drugs for mutant-specific AML. However, many recurrent mutations have been identified across a spectrum from clonal hematopoiesis to myelodysplasia to overt AML, such as effectors of DNA methylation, chromatin modifiers, and spliceosomal machinery. The functional effects of these mutations are the basis for substantial discovery. SUMMARY: Understanding the molecular and pathophysiologic functions of key genes that exert leukemogenic potential is essential towards translating these findings into better treatment for AML.
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Epigenômica/métodos , Leucemia Mieloide Aguda/genética , Humanos , Leucemia Mieloide Aguda/patologia , Metilação , Mutação , Fatores de Transcrição/genéticaRESUMO
The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.
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Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Decitabina/farmacologia , Feminino , Humanos , MasculinoRESUMO
T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Linfocítica Granular Grande/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplantation evaluation, those undergoing transplantation, and the reasons for not undergoing transplantation are unknown. In this retrospective analysis, predefined HCT eligibility and indications criteria were applied to 362 unselected patients with newly diagnosed MDS seen by leukemia faculty between 2008 and 2015 at Memorial Sloan Kettering Cancer Center. Two hundred ninety-four patients (81%) were deemed eligible for transplantation and among these, transplantation was considered indicated in 244 (83%). Of these, 158 of 244 (65%) were referred for transplantation evaluation at a median of 3.9 months from diagnosis. Overall 120 of 362 (33%) underwent transplantation at a median of 7.7 months from diagnosis. Metastatic solid-organ malignancy was the major reason for transplantation ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who did not undergo transplantation, was the major reason for not undergoing transplantation. Factors associated with a lower likelihood of referral for transplantation evaluation included age ≥65 (P < .001), ≥2 comorbidities (P = .008), intermediate-1/low risk MDS (P < .001), <5% blasts at diagnosis (overall P < .001), having Medicare/Medicaid health insurance (P < .001), not being married (P = .017), and diagnosis between 2008 and 2011 (P = .035). On multivariate analysis adjusting for all of the previous factors, diagnosis between 2008 and 2011 (P < .001), age ≥65 (P = .001), and <5% blasts at diagnosis (overall P = .031) were associated with a lower likelihood of referral for transplantation evaluation. Factors associated with a lower likelihood of undergoing transplantation included age ≥65 (P < .001), ≥2 comorbidities (P = .003), intermediate-1/low risk MDS (P < .001), <5% blasts (overall P < .001), very low/low/intermediate risk International Prognostic Scoring System-revised karyotype (P = .018), and having Medicare/Medicaid health insurance (P < .001). In multivariate analysis adjusting for all of the previous factors, age ≥65 (P = .021), presence of ≥2 comorbidities (P = .018), and <5% blasts (overall P = .011) were associated with a lower likelihood of undergoing transplantation. The results highlight that transplantation for MDS remains underutilized, particularly for candidates over the age of 65.
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Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Few studies have examined melanoma and non-melanoma skin cancer (NMSC) incidence rates after a diagnosis of hairy cell leukaemia (HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and Surveillance, Epidemiology and End Results (SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10-year combined melanoma and NMSC skin cancer rate of 11·3%, melanoma 4·4% and NMSC 6·9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4750 SEER patients with HCL, 55 (1·2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios (SIRs) did not show that melanoma was more common in HCL patients versus the general population (SIR 1·3, 95% CI 0·78-2·03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients.
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Leucemia de Células Pilosas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Feminino , Humanos , Incidência , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/enzimologia , Leucemia de Células Pilosas/genética , Masculino , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/epidemiologia , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
In the USA, approximately 26,000 adolescents and young adults (AYAs) aged 15-29 years are diagnosed with cancer every year. The cure rate among this population exceeds 80%, resulting in a growing number of AYA cancer survivors. AYA cancer survivors suffer from a wide range of long-term treatment-related toxicities that adversely affect quality of life and increase the risk of premature death. Therefore, it is important to recognize the unique medical needs of the AYA cancer survivors and develop a cost-effective and systemic approach to screen and prevent cancer treatment-related sequelae and the adverse health outcomes.
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Terapia Combinada/efeitos adversos , Neoplasias Hematológicas/terapia , Glândulas Endócrinas/fisiopatologia , Cardiopatias/etiologia , Cardiopatias/mortalidade , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Pneumopatias/etiologia , Pneumopatias/mortalidade , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/mortalidade , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/secundárioRESUMO
Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in DNMT3A or TET2, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases. Additionally, inflammation may stress the hematopoietic compartment, driving the expansion of mutant clones. While the epidemiologic overlap between CH, hematologic malignancies, and atherosclerotic cardiovascular diseases has been reported, the mechanisms linking these concepts are largely unknown and merit much further investigation. Here, we review studies highlighting the interplay between CH, inflamm-aging, the immune system, and the prevalence of CH in autoimmune diseases.
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Doenças Autoimunes , Hematopoiese Clonal , Humanos , Hematopoiese Clonal/genética , Autoimunidade , Hematopoese/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Mutação , Doenças Autoimunes/genéticaRESUMO
Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92-88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06-55.35, P < 0.001). Currently, the 'zygosity' of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include 'zygosity' status of CHIP mutations and that future prognostication systems should take mutation 'zygosity' into account.
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Hematopoiese Clonal , Neoplasias Hematológicas , Humanos , Mutação , Mutação Puntual , Aberrações Cromossômicas , Neoplasias Hematológicas/genéticaRESUMO
Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay was demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple time points in Vanderbilt University's biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/clonal cytopenia of undetermined significance were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction at both time points. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, mutation co-occurrence and clonal competition between multiple driver mutations were explored.
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Hematopoiese Clonal , Mutação , Humanos , Hematopoiese Clonal/genética , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Adulto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/economia , Análise Custo-Benefício , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Evolução Clonal/genética , Idoso de 80 Anos ou mais , Hematopoese/genéticaRESUMO
ABSTRACT: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, â¼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population.