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Clinical relevance of clonal hematopoiesis in the oldest-old population.

Authors
  • Rossi, Marianna1
  • Meggendorfer, Manja2
  • Zampini, Matteo3
  • Tettamanti, Mauro4
  • Riva, Emma5
  • Travaglino, Erica6
  • Bersanelli, Matteo3
  • Mandelli, Sara4
  • Galbussera, Alessia Antonella4
  • Mosca, Ettore7
  • Saba, Elena3
  • Chiereghin, Chiara3
  • Manes, Nicla3
  • Milanesi, Chiara3
  • Ubezio, Marta8
  • Morabito, Lucio3
  • Peano, Clelia9
  • Soldà, Giulia10
  • Asselta, Rosanna11
  • Duga, Stefano10
  • And 35 more
  • 1 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. , (Italy)
  • 2 MLL Munich Leukemia Laboratory, Munich, Germany. , (Germany)
  • 3 IRCCS Humanitas Research Hospital & Humanitas University, Rozzano - Milan, Italy. , (Italy)
  • 4 Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy. , (Italy)
  • 5 IRCCS Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy. , (Italy)
  • 6 Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy. , (Italy)
  • 7 Institute of Biomedical Technologies, National Research Council (CNR), Segrate, Italy. , (Italy)
  • 8 Cancer Center, IRCCS Humanitas Research Hospital & Humanitas University, Rozzano, Italy. , (Italy)
  • 9 Institute of Genetic and Biomedical Research, UoS of Milan, National Research Council, Rozzano, Italy. , (Italy)
  • 10 Humanitas University, Pieve Emanuele, Milan, Italy. , (Italy)
  • 11 Humanitas University, Pieve Emanuele, Italy. , (Italy)
  • 12 Humanitas University, Rozzano - Milano, Italy. , (Italy)
  • 13 IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy. , (Italy)
  • 14 IRCCS Humanitas Clinical Institute, Rozzano, Italy. , (Italy)
  • 15 University of Milano - Bicocca, Monza, Italy. , (Italy)
  • 16 University of Milano-Bicocca, Milan, Italy. , (Italy)
  • 17 University of Bologna, Bologna, Italy. , (Italy)
  • 18 Humanitas Cancer Center, Milano, Italy. , (Italy)
  • 19 Laboratory of Analysis, Ospedale degli Infermi, Biella, Ponderano (Biella), Italy. , (Italy)
  • 20 Piedmont Cancer Registry, Turin, Italy. , (Italy)
  • 21 Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. , (Italy)
  • 22 University of Milan-Bicocca, Monza, Italy. , (Italy)
  • 23 IRCCS Humanitas Research Hospital & Humanitas University, Rozzano, Italy. , (Italy)
  • 24 Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy. , (Italy)
  • 25 University of Insubria, Varese, Italy. , (Italy)
  • 26 Humanitas Clinical and Research Center IRCCS; Humanitas Univ., Rozzano, Italy. , (Italy)
  • 27 ICO-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain. , (Spain)
  • 28 Department of Hematology and Cellular Therapy, Medical Clinic and Policlinic I, Leipzig University Hospital, Leipzig, Germany. , (Germany)
  • 29 hôpital St Louis, Paris, PARIS, France. , (France)
  • 30 University of Milan, Milan, Italy. , (Italy)
  • 31 Italy. , (Italy)
  • 32 University of Cambridge, Cambridge, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jun 14, 2021
Identifiers
DOI: 10.1182/blood.2021011320
PMID: 34125889
Source
Medline
Language
English
License
Unknown

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms. Copyright © 2021 American Society of Hematology.

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