Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F21%3A10432535" target="_blank" >RIV/00064203:_____/21:10432535 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11130/21:10432535
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=w3cuS4r1O1" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=w3cuS4r1O1</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41591-021-01511-6" target="_blank" >10.1038/s41591-021-01511-6</a>
Alternative languages
Result language
angličtina
Original language name
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Nature Medicine
ISSN
1078-8956
e-ISSN
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Volume of the periodical
27
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
1806-1817
UT code for WoS article
000704942800003
EID of the result in the Scopus database
2-s2.0-85116777637