21 research outputs found
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Concordance for clonal hematopoiesis is limited in elderly twins.
Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero
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Home and away: clonal hematopoiesis in sibling transplants.
CH is the disproportionate clonal expansion of blood stem cells and their progeny driven by leukemia-associated somatic mutations and is associated with an increased risk of hematologic cancers and ischemic cardiovascular disease. Reassuringly, the incidence and genetic drivers of CH, in either donors or recipients, did not seem to differ from that reported for unselected individuals of similar ages. Interestingly, the study also reports on the posttransplant behavior of 5 cases of donor-engrafted CH. This scenario uniquely captures the impact of the transplant procedure and 2 different hematopoietic environments on the behavior of the same CH clone. The authors report greater clonal expansion in recipients with donor-engrafted CH compared with the growth of the same founder clone in donors, thus highlighting important features of CH biology
The PML-RARA fusion is not detectable in historical blood samples of acute promyelocytic leukaemia patients.
P442: DDX41 GERMLINE VARIANTS: POPULATION PREVALENCE, SIGNIFICANCE AND LEUKEMIC EVOLUTION
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Multiparameter prediction of myeloid neoplasia risk.
The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.
Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing
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Multiparameter prediction of myeloid neoplasia risk.
Acknowledgements: This work was funded by an Early Detection Project Grant from Cancer Research UK (EDDCPJT\100010) and a joint grant from the Leukemia and Lymphoma Society (RTF6006-19), and the Rising Tide Foundation for Clinical Cancer Research (CCR-18-500) awarded to G.S.V. The Cambridge Stem Cell Institute is supported by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). W.G.D is funded by a Clinical Research Fellowship from the Cancer Research UK Cambridge Centre (CTRQQR-2021\100012). S.P.K. is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/T043202/1). P.M.Q. is funded by the Miguel Servet Program (CP20/00130). A.S. is funded by Cancer Research UK (grant 29685) and Blood Cancer UK (grant 503). G.S.V. is supported by a Cancer Research UK Senior Cancer Fellowship (C22324/A23015) and work in his laboratory is also funded by the European Research Council, Kay Kendall Leukemia Fund, Blood Cancer UK and the Wellcome Trust. This research was conducted using the UK Biobank resource under approved application 56844. We thank the participants and investigators involved in the UK Biobank resource and in the other genome-wide association studies cited in this work who collectively made this research possible.The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians
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Multiparameter prediction of myeloid neoplasia risk.
Acknowledgements: This work was funded by an Early Detection Project Grant from Cancer Research UK (EDDCPJT\100010) and a joint grant from the Leukemia and Lymphoma Society (RTF6006-19), and the Rising Tide Foundation for Clinical Cancer Research (CCR-18-500) awarded to G.S.V. The Cambridge Stem Cell Institute is supported by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). W.G.D is funded by a Clinical Research Fellowship from the Cancer Research UK Cambridge Centre (CTRQQR-2021\100012). S.P.K. is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/T043202/1). L.M was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), (grant 20125; AIRC 5x1000 project 21267); Cancer Research UK, FC AECC and AIRC under the International Accelerator Award Program (C355/A26819 and 22796). P.M.Q. is funded by the Miguel Servet Program (CP20/00130). A.S. is funded by Cancer Research UK (grant 29685) and Blood Cancer UK (grant 503). G.S.V. is supported by a Cancer Research UK Senior Cancer Fellowship (C22324/A23015) and work in his laboratory is also funded by the European Research Council, Kay Kendall Leukemia Fund, Blood Cancer UK and the Wellcome Trust. This research was conducted using the UK Biobank resource under approved application 56844. We thank the participants and investigators involved in the UK Biobank resource and in the other genome-wide association studies cited in this work who collectively made this research possible.The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians
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Author Correction: Multiparameter prediction of myeloid neoplasia risk.
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.
Funder: British Heart FoundationClonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing