ABSTRACT
The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.
ABSTRACT
INTRODUCTION: Defining the chromosomal and molecular changes associated with myeloid neoplasms (MNs) optimizes clinical care through improved diagnosis, prognosis, treatment planning, and patient monitoring. This review will concisely describe the techniques used to profile MNs clinically today, with descriptions of challenges and emerging approaches that may soon become standard-of-care. AREAS COVERED: In this review, the authors discuss molecular assessment of MNs using non-sequencing techniques, including conventional cytogenetic analysis, fluorescence in situ hybridization, chromosomal genomic microarray testing; as well as DNA- or RNA-based next-generation sequencing (NGS) assays; and sequential monitoring via digital PCR or measurable residual disease assays. The authors explain why distinguishing somatic from germline alleles is critical for optimal management. Finally, they introduce emerging technologies, such as long-read, whole exome/genome, and single-cell sequencing, which are reserved for research purposes currently but will become clinical tests soon. EXPERT OPINION: The authors describe challenges to the adoption of comprehensive genomic tests for those in resource-constrained environments and for inclusion into clinical trials. In the future, all aspects of patient care will likely be influenced by the adaptation of artificial intelligence and mathematical modeling, fueled by rapid advances in telecommunications.
Subject(s)
High-Throughput Nucleotide Sequencing , Humans , High-Throughput Nucleotide Sequencing/methods , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Molecular Diagnostic Techniques/methods , Genomics/methodsABSTRACT
The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.
ABSTRACT
Children with certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in other HM. For some hematopoietic malignancy predisposition (HMP) disorders, specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation (HSCT) can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by an HSCT specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.
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Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.
Subject(s)
Breast Neoplasms , Genetic Predisposition to Disease , Germ-Line Mutation , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/genetics , Breast Neoplasms/genetics , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/epidemiology , Ataxia Telangiectasia Mutated Proteins/genetics , Checkpoint Kinase 2/genetics , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Hematologic Neoplasms/genetics , Genes, BRCA2 , Fanconi Anemia Complementation Group N ProteinABSTRACT
Although numerous barriers for clinical germline cancer predisposition testing exist, the increasing recognition of deleterious germline DNA variants contributing to myeloid malignancy risk is yielding steady improvements in referrals for testing and testing availability. Many germline predisposition alleles are common in populations, and the increasing number of recognized disorders makes inherited myeloid malignancy risk an entity worthy of consideration for all patients regardless of age at diagnosis. Germline testing is facilitated by obtaining DNA from cultured skin fibroblasts or hair bulbs, and cascade testing is easily performed via buccal swab, saliva, or blood. Increasingly as diagnostic criteria and clinical management guidelines include germline myeloid malignancy predisposition, insurance companies recognize the value of testing and provide coverage. Once an individual is recognized to have a deleterious germline variant that confers risk for myeloid malignancies, a personalized cancer surveillance plan can be developed that incorporates screening for other cancer risk outside of the hematopoietic system and/or other organ pathology. The future may also include monitoring the development of clonal hematopoiesis, which is common for many of these cancer risk disorders and/or inclusion of strategies to delay or prevent progression to overt myeloid malignancy. As research continues to identify new myeloid predisposition disorders, we may soon recommend testing for these conditions for all patients diagnosed with a myeloid predisposition condition.
Subject(s)
Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Hematologic Neoplasms , Humans , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapy , Hematologic Neoplasms/diagnosis , Disease ManagementABSTRACT
Not available.
ABSTRACT
SUMMARY: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.
Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Adult , Child , Humans , Myelodysplastic Syndromes/genetics , Gene-Environment Interaction , Genetic Predisposition to Disease , Hematologic Neoplasms/genetics , Germ-Line Mutation , Leukemia, Myeloid, Acute/geneticsABSTRACT
Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients.
Subject(s)
Myelodysplastic Syndromes , Myeloproliferative Disorders , Neoplasms , Humans , Genetic Predisposition to Disease , Penetrance , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/therapy , Germ Cells , Germ-Line Mutation , Intracellular Signaling Peptides and ProteinsABSTRACT
Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/ LP) variants among 1,172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In 8 of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.
Subject(s)
Genetic Predisposition to Disease , Hematologic Neoplasms , Humans , Hematologic Neoplasms/genetics , Hematologic Neoplasms/epidemiology , Male , Female , Age of Onset , Exome Sequencing , Ethnicity/genetics , California/epidemiology , Child, Preschool , Infant, Newborn , Child , Pedigree , Gene Frequency , InfantABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a key treatment option for hematologic malignancies (HMs), although it carries significant risks. Up to 30% of patients relapse after allo-HSCT, of which up to 2% to 5% are donor-derived malignancies (DDMs). DDMs can arise from a germline genetic predisposition allele or clonal hematopoiesis (CH) in the donor. Increasingly, genetic testing reveals that patient and donor genetic factors contribute to the development of DDM and other allo-HSCT complications. Deleterious germline variants in CEBPA, DDX41, GATA2, and RUNX1 predispose to inferior allo-HSCT outcomes. DDM has been linked to donor-acquired somatic CH variants in DNMT3A, ASXL1, JAK2, and IDH2, often with additional new variants. We do not yet have evidence to standardize donor genetic sequencing prior to allo-HSCT. The presence of hereditary HM disorders should be considered in patients with myeloid malignancies and their related donors, and screening of unrelated donors should include family and personal history of cytopenia and HMs. Excellent multidisciplinary care is critical to ensure efficient timelines for screening and necessary discussions among medical oncologists, genetic counselors, recipients, and potential donors. After allo-HSCT, HM relapse monitoring with genetic testing effectively results in genetic sequencing of the donor, as the transplanted hematopoietic system is donor-derived, which presents ethical challenges for disclosure to patients and donors. We encourage consideration of the recent National Marrow Donor Program policy that allows donors to opt-in for notification about detection of their genetic variants after allo-HSCT, with appropriate genetic counseling when feasible. We look forward to prospective investigation of the impact of germline and acquired somatic genetic variants on hematopoietic stem cell mobilization/engraftment, graft-versus-host disease, and DDM to facilitate improved outcomes through knowledge of genetic risk.
Subject(s)
Amides , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Sulfones , Humans , Prospective Studies , Transplantation, Homologous/adverse effects , Neoplasm Recurrence, Local/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Unrelated Donors , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapy , Morbidity , RecurrenceABSTRACT
PURPOSE: To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs). METHODS: The coefficient of variance was calculated from variant allele frequency of next-generation sequencing assays. Variants' likelihood of being germline was ranked on a 1 to 5 scale. Outcomes were examined in patients with such variants. RESULTS: In a pilot set of 33 genes, 89% of grade 1, 77% of grade 2, 62% of grade 3, 52% of grade 4, and 21% of grade 5 variants were confirmed to be germline. Among those, 22% were pathogenic or likely pathogenic in genes recognized as conferring hereditary HM risk, including BRCA1/2, CHEK2, CSF3R, and DDX41. To determine if this approach identified genes with known autosomal dominant inheritance, we analyzed sequential data from 1336 genes in 1135 HM patients. Among unique variants, 16% occurred in hereditary HM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival 2 years after initial molecular testing (78% versus 88%, P = .0037) and increased all-cause mortality compared with those without (hazard ratio 2.02, 95% CI 1.18-3.46, P = .019). CONCLUSION: Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared with those without.
Subject(s)
BRCA1 Protein , Neoplasms , Humans , BRCA1 Protein/genetics , Genetic Predisposition to Disease , BRCA2 Protein/genetics , Germ Cells , Germ-Line Mutation/geneticsSubject(s)
BRCA1 Protein , Humans , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Germ Cells/pathology , Germ-Line Mutation , MutationABSTRACT
Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies. SIGNIFICANCE: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.
Subject(s)
Clonal Hematopoiesis , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Clonal Hematopoiesis/genetics , Adult , Male , Female , Middle Aged , Aged , Young Adult , AdolescentABSTRACT
The recent application of whole exome or whole genome sequencing unveiled a plethora of germline variants predisposing to myeloid disorders, particularly myelodysplastic neoplasms. The presence of such variants in patients with myelodysplastic syndromes has important clinical repercussions for haematopoietic stem-cell transplantation, from donor selection and conditioning regimen to graft-versus-host disease prophylaxis and genetic counselling for relatives. No international guidelines exist to harmonise management approaches to this particular clinical scenario. Moreover, the application of germline testing, and how this informs clinical decisions, differs according to the expertise of individual clinical practices and according to different countries, health-care systems, and legislations. Leveraging the global span of the European Society for Blood and Marrow Transplantation (EBMT) network, we took a snapshot of the current European situation on these matters by disseminating an electronic survey to EBMT centres experienced in myelodysplastic syndromes transplantation. An international group of haematologists, transplantation physicians, paediatricians, nurses, and experts in molecular biology and constitutional genetics with experience in myelodysplastic syndromes contributed to this Position Paper. The panel met during multiple online meetings to discuss the results of the EBMT survey and to establish suggested harmonised guidelines for such clinical situations, which are presented here.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes , Neoplasms , Humans , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/methods , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Surveys and Questionnaires , Transplantation Conditioning/methods , Disease Susceptibility , Graft vs Host Disease/prevention & controlSubject(s)
Anemia, Aplastic , Myeloproliferative Disorders , Neoplasms , Adult , Humans , Prevalence , Bone Marrow , Neoplasms/genetics , Disease SusceptibilityABSTRACT
We now recognize that with aging, hematopoietic stem and progenitor cells (HSPCs) acquire mutations that confer a fitness advantage and clonally expand in a process now termed clonal hematopoiesis (CH). Because CH predisposes to a variety of health problems, including cancers, cardiovascular diseases, and inflammatory conditions, there is intense interest in the inherited alleles associated with the development of CH. DNA variants near TERT, SMC4, KPNA4, IL12A, CD164, and ATM confer the strongest associations. In this review, we discuss our current state of knowledge regarding germline predisposition to CH.
Subject(s)
Clonal Hematopoiesis , Hematopoiesis , Humans , Clonal Hematopoiesis/genetics , Hematopoiesis/genetics , Hematopoietic Stem Cells , Aging/genetics , Mutation , Disease Susceptibility , alpha Karyopherins/geneticsABSTRACT
Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2 deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and elevated IL-6 signaling. As insufficient GM-CSF signaling caused pulmonary alveolar proteinosis and excessive IL-6 signaling promoted bone marrow failure and GATA2 deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.