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

Yasunobu Nagata (), Hideki Makishima, Cassandra M. Kerr, Bartlomiej P. Przychodzen, Mai Aly, Abhinav Goyal, Hassan Awada, Mohammad Fahad Asad, Teodora Kuzmanovic, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Sudipto Mukherjee, Thomas LaFramboise, Aziz Nazha, Mikkael A. Sekeres, Tomas Radivoyevitch, Torsten Haferlach, Seishi Ogawa and Jaroslaw P. Maciejewski ()
Additional contact information
Yasunobu Nagata: Cleveland Clinic
Hideki Makishima: Kyoto University
Cassandra M. Kerr: Cleveland Clinic
Bartlomiej P. Przychodzen: Cleveland Clinic
Mai Aly: Cleveland Clinic
Abhinav Goyal: Cleveland Clinic
Hassan Awada: Cleveland Clinic
Mohammad Fahad Asad: Cleveland Clinic
Teodora Kuzmanovic: Cleveland Clinic
Hiromichi Suzuki: Kyoto University
Tetsuichi Yoshizato: Kyoto University
Kenichi Yoshida: Kyoto University
Kenichi Chiba: The University of Tokyo
Hiroko Tanaka: The University of Tokyo
Yuichi Shiraishi: The University of Tokyo
Satoru Miyano: The University of Tokyo
Sudipto Mukherjee: Taussig Cancer Institute, Cleveland Clinic
Thomas LaFramboise: Case Western Reserve University
Aziz Nazha: Taussig Cancer Institute, Cleveland Clinic
Mikkael A. Sekeres: Taussig Cancer Institute, Cleveland Clinic
Tomas Radivoyevitch: Cleveland Clinic
Torsten Haferlach: MLL Munich Leukemia Laboratory
Seishi Ogawa: Kyoto University
Jaroslaw P. Maciejewski: Cleveland Clinic

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13001-y

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