scholarly journals Driver Mutation Acquisition in Utero and Childhood Followed By Lifelong Clonal Evolution Underlie Myeloproliferative Neoplasms

Blood ◽  
2020 ◽  
Vol 136 (Supplement_2) ◽  
pp. LBA-1-LBA-1
Author(s):  
Nicholas Williams ◽  
Joe Lee ◽  
Luiza Moore ◽  
Joanna E Baxter ◽  
James Hewinson ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clinical Presentation ◽  
Myeloproliferative Neoplasms ◽  
Clonal Expansion ◽  
In Utero ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Patient Specific ◽  
Blood Samples ◽  
Driver Event

Background Recurrent mutations in cancer-associated genes drive tumour outgrowth, however, the timing of driver mutations and the dynamics of clonal expansion remain largely unknown. Philadelphia-negative myeloproliferative neoplasms (MPN) are unique cancers capturing the earliest stages of tumorigenesis through to disease evolution. Most patients harbor JAK2V617F, present as the only driver mutation or occurring in combination with driver mutations in genes such as DNMT3A or TET2. We aimed to identify the timing of driver mutations and clonal dynamics in adult MPN. Method We undertook whole-genome sequencing of individual single-cell derived hematopoietic colonies (n=952) together with targeted resequencing of longitudinal blood samples from 10 patients with MPN who presented with disease between ages 20 and 76 years. We identified 448,553 somatic mutations which were used to reconstruct phylogenetic trees of hematopoiesis, tracing blood cell lineages back to embryogenesis. We timed driver mutation acquisition, characterised the dynamics of tumour evolution and measured clonal expansion rates over the lifetime of patients. Resequencing of bulk blood samples corroborated clonal trajectories and provided population estimates. Results JAK2V617F was acquired in utero or childhood in all patients in whom JAK2V617F was the first or the only driver mutation. Earliest age estimates were within a few weeks post conception, and upper estimates of age of acquisition were between 4.1 months and 11.4 years, despite wide ranging ages of MPN presentation. The mean latency between JAK2V617F acquisition and clinical presentation was 34 years (range 20-54 years). Subsequent driver mutation acquisition, including for JAK2V617F, was separated by decades. Disease latency following acquisition of JAK2V617F as a second driver event was still 12-27 years. DNMT3A mutations, commonly associated with age-related clonal hematopoiesis (CH), occurred as the first driver event, subsequent to mutated-JAK2, and as independent clones representing CH in MPN patients. DNMT3A mutations were also first acquired in utero or childhood, at the earliest 1.2 weeks post conception, and the latest 7.9 weeks of gestation to 7.8 years across 4 patients. A recurrent feature of the clonal landscape in MPN was the observation of similar genetic changes repeatedly occurring in unrelated clones within the same patient. Such 'parallel evolution' was observed for chr9p loss-of-heterozygosity, chr1q+ and mutations in myeloid cancer genes, suggesting that patient-specific factors flavour selective landscapes in MPN. Normal hematopoietic stem cells accumulated ~18 somatic mutations/year, however, mutant clones, particularly those with mutant-JAK2, acquired 1.5-5.5 excess mutations/ year and had shorter telomeres, reflecting increased cell divisions during clonal expansion. We modelled the rates of clonal expansion and found that they varied substantially, both across patients and within individuals. In one patient, an in utero acquired DNMT3A-mutated clone expanded slowly at <10%/year, taking 30 years to reach a clonal fraction of 1%, whilst a clone with mutated-JAK2, -DNMT3A and -TET2 expanded at >200%/year, doubling in size every 7 months. JAK2V617F as a single driver mutation also expanded variably across patients, highlighting that other factors, which may include germline, cytokine or stem cell differences between individuals, also influence selection for driver mutations. JAK2V617F associated clonal expansion rates in MPN were greater than that reported for JAK2-CH. Furthermore, rates of expansion in the cohort predicted time to clinical presentation, more so than age of mutation acquisition or tumour burden at diagnosis. This suggests that JAK2-mutant clonal expansion rates determine both if and when clinical manifestations occur. Driver mutations and rates of clonal expansion would have been detectable in blood one to four decades before clinical presentation. Conclusions MPN originate from driver mutation acquisition very early in life, even before birth, with life-long clonal expansion and evolution, establishing a new paradigm for blood cancer development. Early detection of mutant-JAK2 together with determination of clonal expansion rates could provide opportunities for early interventions aimed at minimising thrombotic risk and targeting the mutant clone in at risk individuals. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution.

2020 ◽  
Author(s):  
Jyoti Nangalia ◽  
Nicholas Williams ◽  
Joe Lee ◽  
Luiza Moore ◽  
E Baxter ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Myeloproliferative Neoplasms ◽  
Phylogenetic Reconstruction ◽  
Clonal Expansion ◽  
In Utero ◽  
Driver Mutation ◽  
Driver Mutations ◽  
New Paradigm ◽  
Blood Cancer ◽  
Age Related

Abstract Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation in these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients. DNMT3A mutations, which are associated with age-related clonal haematopoiesis, were also acquired in utero or childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency between JAK2V617F acquisition and clinical presentation was 34 years (range 20-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth trajectories drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.

scholarly journals Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution

2020 ◽  
Author(s):  
Nicholas Williams ◽  
Joe Lee ◽  
Luiza Moore ◽  
E Joanna Baxter ◽  
James Hewinson ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Phylogenetic Reconstruction ◽  
Clonal Expansion ◽  
In Utero ◽  
Driver Mutation ◽  
Driver Mutations ◽  
New Paradigm ◽  
Age Related

ABSTRACTMutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation in these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients. DNMT3A mutations, which are associated with age-related clonal haematopoiesis, were also acquired in utero or childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency between JAK2V617F acquisition and clinical presentation was 31 years (range 12-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth and evolution drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.

scholarly journals Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2100
Author(s):  
Lasse Kjær
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Clinical Intervention ◽  
Driver Mutation ◽  
Response Monitoring ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Disease Biology ◽  
Background Population ◽  
The Impact

Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

scholarly journals Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1513-1521 ◽  
Author(s):  
Luca Malcovati ◽  
Elli Papaemmanuil ◽  
Ilaria Ambaglio ◽  
Chiara Elena ◽  
Anna Gallì ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clinical Decision Making ◽  
Myeloproliferative Neoplasms ◽  
Clinical Decision ◽  
Driver Mutations ◽  
Myeloid Neoplasms ◽  
Key Points ◽  
Distinct Disease ◽  
Disease Entities

Key Points Different driver mutations have distinct effects on phenotype of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Accounting for driver mutations may allow a classification of these disorders that is considerably relevant for clinical decision-making.

scholarly journals Profile of Myeloproliferative Neoplasms in Kuwait: Population-Based Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5373-5373
Author(s):  
Mazyad Jamal Almazyad ◽  
Aisha S Alwehaib ◽  
Salem Alshemmari
Keyword(s):  
High Risk ◽  
Similar Pattern ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Population Based ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Positive Finding ◽  
Population Based Study ◽  
Arms Pcr

Introduction Myeloproliferative neoplasms (MPNs) are a group of hematopoietic disorders of stem-cell origin, characterized by mutations that disrupt hematopoietic signal-transduction pathways. The Middle East lacks an MPN registry representative of the disease in our area. Here we report on the epidemiology of these neoplasms in our area, including phenotype, clinical features and relevant outcomes. Methods This population-based study reports various demographic characteristics and clinical attributes of all suspected and confirmed MPN patients from all over Kuwait referred to the research hematology lab at Kuwait University & cytogenetic lab in Kuwait Cancer Control Centre (KCCC) during the period from 2007 to 2018. Molecular determination of the patients' driver mutation status currently relies on ARMS-PCR. Confirming a diagnosis follows the WHO criteria, and its refinements, for the diagnosis of MPNs. Data entry and analysis was performed using SPSS (v.22) software. Results Most patients are ≥ 40 years old (79.8%), with a median age of 55 years. Gender distribution is almost equal, with ethnic categorization as Kuwaiti and Non-Kuwaiti showing a similar pattern. ET is the most common diagnosis (40.1%), followed by PRV (32.3%). JAK2 V617F mutation is reported positive in 89.7% of cases, followed by CALR in 8.0% of MPNs. The incidence of MPNs ranged from 0.5 to 2.1 per 100,000 in 2007 through 2018. The lowest rate was recorded in 2007 (0.511) and the highest was observed in 2011 and 2016 (2.417 and 2.101, respectively). The increase in 2011 is likely due to the introduction of a more sensitive technique using ARMS-PCR for the diagnosis of MPNs, whereas the increase in 2017 may be explained by the publication of WHO 2016 modified criteria. Moreover, throughout the years, the distribution of MPNs in different age groups showed similar pattern, with the highest incidence in patients aged ≥ 60. Driver mutations can fit with a general increase in incidence from 2007-2017, which may be attributed to increased awareness among treating physicians asking suspected cases to screen for MPNs using molecular techniques.One hundred and twenty-four (18.5%) cases were documented to have a prior history of thrombosis, with roughly equal distribution between arterial and venous sites. A large proportion (89.5%) of the thrombotic events occurred in those who are ≥ 40 years old, with most events being associated with ET (34.7%) and PRV (33.1%). Almost one-third of cases of thrombosis were associated with undetermined MPN diagnosis. Participating patients were categorized as either low or high risk for thrombotic events, with the latter being defined as age ≥ 55 years and the presence of a previous thrombotic event. The results demonstrate that a total of 46 cases were defined as high risk, most of them being associated with ET (20 cases) and PRV (19 cases). A statistically significant association was reported between gender and site of occurrence of thrombotic events, with males having more arterial thromboses, and females were documented to have more venous thromboses. Conclusion JAK2 V617F driver mutation is the most common positive finding in the participating patients. Roughly one-fifth of the participants encountered thrombotic events, and the site of thrombosis is associated with gender, demonstrating statistical significance. These results should warrant a more thorough evaluation of MPNs in Kuwait to provide a better understanding of its epidemiology. This can be achieved through optimized documentation of patients' data, and testing for additional novel driver mutations and transformation; as well as encourage physicians in primary care centers to refer suspected cases for molecular diagnosis. Disclosures No relevant conflicts of interest to declare.

Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden

2016 ◽  
pp. e324-e335 ◽  
Author(s):  
Ruben A. Mesa ◽  
Francesco Passamonti
Keyword(s):  
Polycythemia Vera ◽  
Disease Burden ◽  
Myeloproliferative Neoplasms ◽  
Individualized Medicine ◽  
Genetic Mutation ◽  
Driver Mutations ◽  
Patient Specific ◽  
Vascular Events ◽  
Line Therapy ◽  
Definitive Therapy

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of “individualizing” care for patients with MPNs.

scholarly journals A Cure for Paroxysmal Nocturnal Hemoglobinuria Using Molecular Targeted Therapy Specific to a Driver Mutation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1215-1215 ◽  
Author(s):  
Takamasa Katagiri ◽  
Ryo Tominaga ◽  
Keisuke Kataoka ◽  
Akio Maeda ◽  
Hiroshi Gomyo ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Molecular Targeted Therapy ◽  
Clonal Expansion ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Hematopoietic Progenitor Cell ◽  
Complete Disappearance ◽  
Molecular Response ◽  
Hematopoietic Stem

Abstract Background: The clonal expansion of PIGA mutant hematopoietic stem cells (HSCs) can be induced by secondary driver mutations in genes such as HMGA2 and JAK2 in some patients with paroxysmal nocturnal hemoglobinuria (PNH). Theoretically, this type of PNH may be cured by molecular targeted therapy if the therapy is specific for the driver mutations and can eliminate PIGA mutant HSCs that acquired a proliferative advantage. However, this theory has not been proven because of the lack of an appropriate targeted therapy for known driver mutations responsible for clonal expansion of PIGA mutant HSCs. We recently treated a case of PNH complicated by chronic myeloid leukemia (CML) with nilotinib and observed a complete molecular response of CML followed by a complete disappearance of glycosylphosphatidylinositol-anchored protein-deficient (GPI-AP-, PNH-type) cells after 19 months of treatment. Case report: The patient, a 27-year-old Japanese woman, developed severe anemia with leukocytosis and thrombocytosis in 2013. The laboratory findings on admission were as follows: white blood cell count of 18.7x109/L with 1.7% stab neutrophils, 5.4% segmented neutrophils, 9.3% basophils, 1.3% promyelocytes, 5.0% myelocytes, 3.0% metamyelocytes, 18.0% lymphocytes and 0.7% blasts; hemoglobin (Hb)=6.0 g/dL, platelets=1,000x109/L, 20.0% reticulocytes, total/direct bilirubin=1.9/0.3 mg/dL, LDH=1963 IU/L and haptoglobin <10 mg/dL. A high-sensitivity flow cytometry analysis of the patient's peripheral blood at diagnosis revealed that 99.2% of granulocytes, 75.7% of erythrocytes and 99.3% of monocytes were GPI-AP-, while no T cells, B cells or NK cells had the PNH-phenotype (Figure 1A). This GPI-AP- cell distribution pattern was in sharp contrast to that of a patient with typical PNH who showed various percentages of GPI-AP- cells in all lineages of leukocytes and erythrocytes (Figure 1B). A fluorescent in situ hybridization analysis showed that 98.0% of the patient's granulocytes were BCR-ABL gene-fusion positive. Deep sequencing of leukocytes obtained at diagnosis showed a G279T (Q93H) mutation in exon 4 of the PIGA gene. The patient was diagnosed with PNH complicated by CML in the chronic phase, and was treated with nilotinib at 400 mg/day. The percentage of GPI-AP- cells rapidly decreased in response to nilotinib, with 0.02% GPI-AP- granulocytes after six months of nilotinib therapy when the patient's BCR-ABL mRNA decreased to 0.007%. BCR-ABL mRNA decreased to less than 0.0035% 15 months after therapy; however, small populations of GPI-AP- granulocytes (0.01%) and erythrocytes (0.005%) were still detected at this time (Figure 1A). GPI-AP- cells became undetectable after 19 months of nilotinib therapy, suggesting that the BCR/ABL fusion occurred in a subclone of a PIGA mutant hematopoietic progenitor cell (HPC). The patient was continuing nilotinib as of August 2015 without any signs of an increase in the BCR-ABL mRNA copy number. Conclusions: This case indicates the BCR-ABL fusion can be a driver mutation capable of inducing the clonal expansion of PIGA mutant clones. More importantly, the origin of PNH in our case proved to be a minor HPC clone with a PIGA mutation, suggesting that PNH can be derived from an HPC with a limited life span only if a potent second hit occurs in the PIGA mutant HPC. The identification of driver mutations in patients with PNH may therefore lead to the development of targeted therapy capable of curing PNH. Disclosures No relevant conflicts of interest to declare.

Genomic alterations underlying spinal metastases in pediatric H3K27M-mutant pineal parenchymal tumor of intermediate differentiation: case report

2020 ◽  
Vol 25 (2) ◽  
pp. 121-130 ◽  
Author(s):  
Elena I. Fomchenko ◽  
E. Zeynep Erson-Omay ◽  
Adam J. Kundishora ◽  
Christopher S. Hong ◽  
Ava A. Daniel ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clinical Presentation ◽  
Spinal Metastases ◽  
Copy Number Variations ◽  
Chromosome 17 ◽  
Driver Mutations ◽  
Dismal Prognosis ◽  
Whole Exome ◽  
Clonality Analysis ◽  
Surgical Options

Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient’s PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.

High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2992-2996 ◽  
Author(s):  
Jeffrey W. Taub ◽  
Mark A. Konrad ◽  
Yubin Ge ◽  
John M. Naber ◽  
Jackie S. Scott ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Newborn Screening ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Leukemia Cells ◽  
Patient Specific ◽  
Childhood All ◽  
Blood Samples ◽  
Leukemic Clone ◽  
Study Support

Abstract The detection of leukemia cells on newborn genetic screening cards (“Guthrie cards”) of a small group of patients and several sets of identical twins developing acute lymphoblastic leukemia (ALL) with identical phenotypic and chromosomal markers has provided evidence that childhood ALL cases may arise in utero. We conducted a retrospective study of a randomly selected group of childhood B-precursor ALL patients to determine the frequency of the presence of “leukemic” clones prenatally in ALL cases by testing newborn screening cards. The 17 ALL patients analyzed had a median age of 46 months (range, 18 months to 13 years) and had median presenting white blood cell (WBC) counts of 10 950/μL (range, 2900-70 300/μL) at diagnosis. A clonal rearrangement of the immunoglobulin heavy chain (IgH) gene was identified in diagnostic lymphoblasts and sequenced and patient-specific primers were used to amplify DNA from blood samples on the patient's newborn screening cards. Twelve of the 17 (71%) analyzed newborn cards had detectable IgH rearrangements amplified by seminested polymerase chain reaction. DNA sequencing confirmed that the IgH rearrangements detected matched the IgH sequences identified from diagnostic leukemia cells, indicating the presence of a “leukemic” clone at birth. There were no differences in age or presenting WBC counts between the cases with or without positive newborn screening cards. All 6 patients with hyperdiploid ALL had detectable “leukemic” clones on their cards. The results of our study support the notion that a high proportion of childhood B-precursor ALL cases arise in utero, although postnatal events are also important factors in leukemogenesis.

scholarly journals Worse Outcomes in Males with MPN Are Associated with Qualitative and Quantitative Differences in Non-Driver Mutational Burden

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 837-837
Author(s):  
Theodoros Karantanos ◽  
Evan M Braunstein ◽  
Shruti Chaturvedi ◽  
Jerry L. Spivak ◽  
Linda Resar ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cox Regression ◽  
Myeloproliferative Neoplasms ◽  
Multivariable Analysis ◽  
Jak2 V617f ◽  
Driver Mutation ◽  
Molecular Characteristics ◽  
Free Survival ◽  
Mutational Burden ◽  
Male Sex

INTRODUCTION: The chronic myeloproliferative neoplasms (MPN) have variable courses and outcomes despite similar driver mutations. We have found that males present more commonly with primary myelofibrosis (PMF) as opposed to essential thrombocytosis (ET) independently of driver mutation and age, and have demonstrated the independent negative impact of male sex in transformation to secondary MF (sMF), AML, and overall survival. The aim of this study was to examine both driver and non-driver mutational burden as a factor in presentation and outcome in the MPN. PATIENTS AND METHODS: 652 individuals with ET, PV or PMF (394 females and 258 males; 311 with ET, 252 with PV and 89 with PMF) were enrolled in our prospective observational cohort between 2005-2019, with a median follow up of 9 years (Q25-75% 4, 15 years). All JAK2 V617F -positive patients were genotyped for quantitative JAK2 V617F variant allele fractions (VAF) at enrollment and over time, and 76 patients (41 females and 35 males, 43 with ET, 23 with PV and 10 with PMF) had additional sequencing, examining 63 genes implicated in myeloid neoplasms. Multivariable cox regression was used to examine the associations of sex, age and molecular characteristics with venous thrombosis, cerebrovascular events, and MF/AML transformation. Univariate cox regression and Kaplan-Meier (KM) were used to assess the effect of JAK2 V617F VAF change/year on survival. Multivariable logistic regression was used to evaluate the associations of sex, age, phenotype and number of additional somatic mutations. RESULTS: Venous thromboembolism was less common in males (OR 0.44, 95% CI 0.26 - 0.76, P=0.004) independent of age, driver mutation, and MPN diagnosis. Arterial ischemic events were more common in males (OR 1.86, 95% CI 1.14 - 3.02, P=0.013) independent of driver mutation, and initial MPN diagnosis. Male sex was a predictor of sMF transformation (HR 1.5, 95% CI 1.02 - 2.2, P=0.04) independent of age and phenotype at diagnosis, and driver mutation, and transformation to AML (HR 2.63, 95% CI 1.21 - 5.67, P=0.014) independent of age at diagnosis and driver mutation. These results were confirmed with KM analysis (P=0.013 and P=0.018 respectively) (Figures 1A - B). The neutrophil JAK2 V617F VAF or its change/year were not associated with survival in the entire cohort (HR 1, 95% CI 0.99 - 1.01, P=0.082 and HR 1.05, 95% CI 0.97 - 1.12, P=0.22 respectively). However, JAK2 V617F VAF or its change/year was associated with survival in females (HR 1.01, 95% CI 1 - 1.02, P=0.044 and HR 1.12, 95% CI for HR 1.01 - 1.25, P=0.04 respectively). KM analysis confirmed that yearly increases of JAK2 V617F VAF higher than 0.5/year were associated with worse survival only in females (P=0.013). Multivariable analysis showed that males had a higher number of additional somatic mutations (Coef 1.14, 95% CI 0.15 - 2.13, P=0.024) independent of age and diagnosis at the time of sequencing (Figures 1C). Analysis of individual mutations (Figure 1C) showed that males have higher prevalence of ASXL1 (22.9% vs 2.4%, P=0.01) and DNMT3A mutations (11.4% versus 7.3%), mutations associated with MDS/MPN phenotype (CBL, KRAS, EZH2, U2AF1), (22.9% vs 7.3%) and concurrent JAK2 and CALR mutations (11.4% vs 0%, P=0.04). CONCLUSIONS: Males with MPN have higher risk of sMF and AML transformation accounting for their worse survival. Males with MPN are less dependent on the JAK2 V617F VAF as an outcome determinant compared to females, but instead carry a higher risk non-driver mutational burden compared to females. Both quantity and quality of non-driver mutational burden differ between males and females with MPN, with males harboring higher risk burden that underlies higher risk presentation and outcomes. Figure 1. Males have higher frequency of somatic mutations additional to their MPN driver mutation independent of age and MPN diagnosis at the time of the NGS. A. KM analysis showing that males have shorter sMF-free survival (P=0.013). B. KM analysis showing that males have shorter AML-free survival (P=0.018). C. The percentage of males with 1 or more additional somatic mutations is higher compared to females across all MPN at the time of the NGS (ET, PV, PMF, sMF). D. The analysis of the specific additional somatic mutations in our cohort showed that males have higher frequency of high-risk CHIP-related mutations (ASXL1, DNMT3A), mutations in genes related to MDS/MPN phenotype and concurrent mutations in JAK2 and CALR. Disclosures Chaturvedi: Shire/Takeda: Research Funding; Alexion: Consultancy; Sanofi: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document