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Blood Cancer Discovery Jan 2024NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML. NPM1-mutated AML is recognizable by molecular techniques and... (Review)
Review
UNLABELLED
NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML. NPM1-mutated AML is recognizable by molecular techniques and immunohistochemistry, which, when combined, can solve difficult diagnostic problems (including identification of myeloid sarcoma and NPM1 mutations outside exon 12). According to updated 2022 European LeukemiaNet (ELN) guidelines, determining the mutational status of NPM1 (and FLT3) is a mandatory step for the genetic-based risk stratification of AML. Monitoring of measurable residual disease (MRD) by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage. Here, we review the criteria for appropriate diagnosis and molecular monitoring of NPM1-mutated AML.
SIGNIFICANCE
NPM1-mutated AML represents a distinct entity in the 2022 International Consensus Classification and 5th edition of World Health Organization classifications of myeloid neoplasms. The correct diagnosis of NPM1-mutated AML and its distinction from other AML entities is extremely important because it has clinical implications for the management of AML patients, such as genetic-based risk stratification according to 2022 ELN. Monitoring of MRD by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage, e.g., whether or not to perform allogeneic hematopoietic stem cell transplantation.
Topics: Adult; Humans; Nuclear Proteins; Nucleophosmin; Leukemia, Myeloid, Acute; Mutation; Risk Factors
PubMed: 37917833
DOI: 10.1158/2643-3230.BCD-23-0144 -
Cell Feb 2024This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The... (Review)
Review
This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The field has witnessed tremendous technological advances from microarrays to short-read sequencing and now long-read sequencing. Each technology has provided genome-wide access to different classes of human genetic variation. We are now on the verge of comprehensive variant detection of all forms of variation for the first time with a single assay. We predict that this transition will further transform our understanding of human health and biology and, more importantly, provide novel insights into the dynamic mutational processes shaping our genomes.
Topics: Humans; Genomics; Germ-Line Mutation; Mutation; Technology; Genomic Structural Variation
PubMed: 38290514
DOI: 10.1016/j.cell.2024.01.002 -
British Journal of Haematology Aug 2023Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs)...
Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.
Topics: Humans; fms-Like Tyrosine Kinase 3; Mutation; Leukemia, Myeloid, Acute; Point Mutation; Hematologic Neoplasms
PubMed: 37246158
DOI: 10.1111/bjh.18877 -
Cancer Cell Aug 2023Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated...
Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.
Topics: Male; Humans; Mutagenesis; Mutation; Prostatic Neoplasms; Receptors, Androgen; Chromosomal Proteins, Non-Histone; Heterogeneous-Nuclear Ribonucleoproteins; Cytidine Deaminase; Minor Histocompatibility Antigens; Polycomb Repressive Complex 1
PubMed: 37478850
DOI: 10.1016/j.ccell.2023.06.010 -
Blood Advances Aug 2023TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional...
TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.
Topics: Humans; Chromothripsis; Mutation; Chromosome Aberrations; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Myelodysplastic Syndromes; Genomics; Tumor Suppressor Protein p53
PubMed: 37339484
DOI: 10.1182/bloodadvances.2023010156 -
Cancer Cell Oct 2023The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of...
The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of lung cancer. To induce TMB in lung GEMMs, we expressed an ultra-mutator variant of DNA polymerase-E (POLE) in lung epithelial cells. Introduction of Pole allele into Kras and Kras; p53 (KP) models significantly increase their TMB. Immunogenicity and sensitivity to immune checkpoint blockade (ICB) induced by Pole is partially dependent on p53. Corroborating these observations, survival of NSCLC patients whose tumors have TP53 mutations is shorter than those with TP53 with immunotherapy. Immune resistance is in part through reduced antigen presentation and in part due to mutational heterogeneity. Total STING protein levels are elevated in Pole mutated KP tumors creating a vulnerability. A stable polyvalent STING agonist or p53 induction increases sensitivity to immunotherapy offering therapeutic options in these polyclonal tumors.
Topics: Mice; Animals; Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53; Carcinoma, Non-Small-Cell Lung; Mutation
PubMed: 37774698
DOI: 10.1016/j.ccell.2023.09.006 -
Microbiology (Reading, England) Nov 2023Genetic mutation, which provides the raw material for evolutionary adaptation, is largely a stochastic force. However, there is ample evidence showing that mutations can... (Review)
Review
Genetic mutation, which provides the raw material for evolutionary adaptation, is largely a stochastic force. However, there is ample evidence showing that mutations can also exhibit strong biases, with some mutation types and certain genomic positions mutating more often than others. It is becoming increasingly clear that mutational bias can play a role in determining adaptive outcomes in bacteria in both the laboratory and the clinic. As such, understanding the causes and consequences of mutation bias can help microbiologists to anticipate and predict adaptive outcomes. In this review, we provide an overview of the mechanisms and features of the bacterial genome that cause mutational biases to occur. We then describe the environmental triggers that drive these mechanisms to be more potent and outline the adaptive scenarios where mutation bias can synergize with natural selection to define evolutionary outcomes. We conclude by describing how understanding mutagenic genomic features can help microbiologists predict areas sensitive to mutational bias, and finish by outlining future work that will help us achieve more accurate evolutionary forecasts.
Topics: Mutation; Mutagenesis; Bacteria; Bias; Biological Evolution
PubMed: 37943288
DOI: 10.1099/mic.0.001404 -
Nature Genetics Dec 2023Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome...
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.
Topics: Humans; Aged; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Mutation; Hematopoietic Stem Cells
PubMed: 37932435
DOI: 10.1038/s41588-023-01555-z -
Development, Growth & Differentiation Jan 2024Neurons born during the fetal period have extreme longevity and survive until the death of the individual because the human brain has highly limited tissue regeneration.... (Review)
Review
Neurons born during the fetal period have extreme longevity and survive until the death of the individual because the human brain has highly limited tissue regeneration. The brain is comprised of an enormous variety of neurons each exhibiting different morphological and physiological characteristics and recent studies have further reported variations in their genome including chromosomal abnormalities, copy number variations, and single nucleotide mutations. During the early stages of brain development, the increasing number of neurons generated at high speeds has been proposed to lead to chromosomal instability. Additionally, mutations in the neuronal genome can occur in the mature brain. This observed genomic mosaicism in the brain can be produced by multiple endogenous and environmental factors and careful analyses of these observed variations in the neuronal genome remain central for our understanding of the genetic basis of neurological disorders.
Topics: Humans; DNA Copy Number Variations; Mutation; Mosaicism; Genomics; Neurons
PubMed: 37855730
DOI: 10.1111/dgd.12898 -
Trends in Molecular Medicine Jul 2023Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations... (Review)
Review
Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations may vary between cancer types and patients, can remain latent for a long time and become drivers at particular cancer stages, or may drive oncogenesis only in conjunction with other mutations. The high mutational, biochemical, and histological tumor heterogeneity makes driver mutation identification very challenging. In this review we summarize recent efforts to identify driver mutations in cancer and annotate their effects. We underline the success of computational methods to predict driver mutations in finding novel cancer biomarkers, including in circulating tumor DNA (ctDNA). We also report on the boundaries of their applicability in clinical research.
Topics: Humans; Neoplasms; Mutation; Carcinogenesis; Biomarkers, Tumor
PubMed: 37076339
DOI: 10.1016/j.molmed.2023.03.007