Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes

Yasunobu Nagata,Seishi Ogawa,Cassandra M Kerr ,Abhinav Goyal,Kenichi Yoshida,Teodora Kuzmanovic,Mai Aly,Hassan Awada,Tomas Radivoyevitch,Tetsuichi Yoshizato,Mikkael A Sekeres,Yuichi Shiraishi,Kenichi Chiba,Hideki Makishima,Aziz Nazha,Hiroko Tanaka,Thomas Laframboise,Satoru Miyano,Sudipto Mukherjee,Mohammad Asad ,Bartlomiej Przychodzen ,Torsten Haferlach,Hiromichi Suzuki,Jaroslaw P Maciejewski

doi:10.1038/s41467-019-13001-y

Yasunobu Nagata, Seishi Ogawa + Show 22 more

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https://doi.org/10.1038/s41467-019-13001-y

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Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.

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Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations
Our goal was to study the clonal architecture of MDS to clarify the impact of mutations and their combinations on clinical phenotypes, and to assess the role of clonal hematopoiesis (CH)-associated mutations in frank MDS
We generated a well-annotated large cohort of untreated MDS patients that would allow us to account for the tremendous clinical heterogeneity and the corresponding genotypic diversity

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Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS. Heretofore, mapping mutation-state combinatorics to phenotypes have demonstrated a tremendous complexity, but have not yielded generalizable rules; correlations with classical morphologic subdivisions have been weak[26] Clustering mutations by their rank in the clonal hierarchy or ancestral hit-deducted derivation as de novo or CH-related disease may illuminate disease teleology and consequent clinical outcome. The Beta Binomial emission model implemented in PyClone has been developed to recapitulate clonal hierarchy[28] Limitations aside, these approaches provide hierarchical ranks of mutations that reflect clonal succession from primary/dominant hits to subsequent secondary hits

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