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

• Published in: Nature medicine Vol. 27; no. 10; pp. 1806 - 1817
• Main Authors: Sahoo, Sushree S., Pastor, Victor B., Goodings, Charnise, Voss, Rebecca K., Kozyra, Emilia J., Szvetnik, Amina, Noellke, Peter, Dworzak, Michael, Starý, Jan, Locatelli, Franco, Masetti, Riccardo, Schmugge, Markus, De Moerloose, Barbara, Catala, Albert, Kállay, Krisztián, Turkiewicz, Dominik, Hasle, Henrik, Buechner, Jochen, Jahnukainen, Kirsi, Ussowicz, Marek, Polychronopoulou, Sophia, Smith, Owen P., Fabri, Oksana, Barzilai, Shlomit, de Haas, Valerie, Baumann, Irith, Schwarz-Furlan, Stephan, Niewisch, Marena R., Sauer, Martin G., Burkhardt, Birgit, Lang, Peter, Bader, Peter, Beier, Rita, Müller, Ingo, Albert, Michael H., Meisel, Roland, Schulz, Ansgar, Cario, Gunnar, Panda, Pritam K., Wehrle, Julius, Hirabayashi, Shinsuke, Derecka, Marta, Durruthy-Durruthy, Robert, Göhring, Gudrun, Yoshimi-Noellke, Ayami, Ku, Manching, Lebrecht, Dirk, Erlacher, Miriam, Flotho, Christian, Strahm, Brigitte, Niemeyer, Charlotte M., Wlodarski, Marcin W.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2021; Nature Publishing Group
• Subjects: 631/208/212/2304; 692/308/2056; Abnormalities; Adolescent; Analysis; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone Marrow Cells - metabolism; Cancer and Oncology; Cancer och onkologi; Cancer Research; Care and treatment; CD34 antigen; Cell death; Child; Child, Preschool; Clinical Medicine; Clonal Evolution - genetics; Clonal Hematopoiesis - genetics; Clustering; Development and progression; Diagnosis; Disorders; DNA sequencing; Female; GATA2 Transcription Factor - genetics; Gene mutations; Germ-Line Mutation - genetics; Health aspects; HEK293 Cells; Hematologi; Hematology; Hematopoiesis; High-Throughput Nucleotide Sequencing; Humans; Infant; Infectious Diseases; Intracellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolic Diseases; Molecular Medicine; Monosomy; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Neurosciences; Observations; Patients; Pediatrics; Phenotypes; Single-Cell Analysis; Tumor Suppressor Proteins - genetics; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-021-01511-6

Germline SAMD9 and SAMD9L mutations ( SAMD9/9L mut ) 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 SAMD9/9L mut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L mut 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 SAMD9/9L mut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L mut suppressed HEK293 cell growth, and mutations expressed in CD34 +  cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L mut 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 SAMD9/9L mut ). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L mut 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.