Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Autor: Sahoo S. S., Pastor V. B., Goodings C., Voss R. K., Kozyra E. J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O. P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B. D., Smith O., Haas V. D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P. D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R. D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L. M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M. L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M. R., Sauer M. G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M. H., Meisel R., Schulz A., Cario G., Panda P. K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C. M., Wlodarski M. W.
Přispěvatelé: Sahoo S.S., Pastor V.B., Goodings C., Voss R.K., Kozyra E.J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O.P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B.D., Smith O., Haas V.D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P.D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R.D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L.M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M.L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M.R., Sauer M.G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M.H., Meisel R., Schulz A., Cario G., Panda P.K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C.M., Wlodarski M.W., Clinical Genetics
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Oncology
Male
medicine.medical_specialty
Monosomy
Adolescent
Somatic cell
Medizin
Bone Marrow Cells
Kaplan-Meier Estimate
General Biochemistry
Genetics and Molecular Biology
Germline
Article
Clonal Evolution
Germline mutation
SDG 3 - Good Health and Well-being
Internal medicine
medicine
Humans
Child
Germ-Line Mutation
Chromosome 7 (human)
Cytopenia
clonal hemopoiesis
business.industry
Myelodysplastic syndromes
Tumor Suppressor Proteins
Intracellular Signaling Peptides and Proteins
High-Throughput Nucleotide Sequencing
Infant
General Medicine
medicine.disease
GATA2 Transcription Factor
SAMD9 and SAMD9L mutations
Pediatric Myelodysplastic syndromes
medicine.anatomical_structure
HEK293 Cells
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Child
Preschool
Myelodysplastic Syndromes
Female
Bone marrow
Clonal Hematopoiesis
Single-Cell Analysis
business
Zdroj: Nat Med
Nature Medicine, 27(10), 1806-1817. Nature Publishing Group
Sahoo, S S, Pastor, V B, Goodings, C, Voss, R K, Kozyra, E J, Szvetnik, A, Noellke, P, Dworzak, M, Starý, J, Locatelli, F, Masetti, R, Schmugge, M, De Moerloose, B, Catala, A, Kállay, K, Turkiewicz, D, Hasle, H, Buechner, J, Jahnukainen, K, Ussowicz, M, Polychronopoulou, S, Smith, O P, Fabri, O, Barzilai, S, de Haas, V, Baumann, I, Schwarz-Furlan, S, Niewisch, M R, Sauer, M G, Burkhardt, B, Lang, P, Bader, P, Beier, R, Müller, I, Albert, M H, Meisel, R, Schulz, A, Cario, G, Panda, P K, Wehrle, J, Hirabayashi, S, Derecka, M, Durruthy-Durruthy, R, Göhring, G, Yoshimi-Noellke, A, Ku, M, Lebrecht, D, Erlacher, M, Flotho, C, Strahm, B, Niemeyer, C M, European Working Group of MDS in Children (EWOG-MDS) & Wlodarski, M W 2021, ' Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes ', Nature Medicine, vol. 27, no. 10, pp. 1806-1817 . https://doi.org/10.1038/s41591-021-01511-6
ISSN: 1078-8956
Popis: Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.
Databáze: OpenAIRE
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