Journal Article

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

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

2019

Overview

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. Stepwise acquisition of mutations gives rise to myelodysplastic syndrome (MDS) in older adults. Here, the authors infer the clonal hierarchy of 1809 MDS patients, revealing insights into the evolution of dominant/secondary mutations and how these impact clinical phenotypes like leukemic progression and therapy response.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/47 / 631/208/69 / 631/67/1990/1673 / Aged / Architecture / Disorders / Female / Hematopoiesis - genetics / Humanities and Social Sciences / Humans / Invariants / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Male / Medical prognosis / Morphology / multidisciplinary / Mutation / Myelodysplastic syndrome / Myelodysplastic syndromes / Myelodysplastic Syndromes - drug therapy / Myelodysplastic Syndromes - etiology / Myelodysplastic Syndromes - genetics / Myelodysplastic Syndromes - pathology / Older people / p53 Protein / Phenotype / Phenotypes / Phosphoproteins - genetics / Primary Myelofibrosis - genetics / RNA Splicing Factors - genetics / Science / Science (multidisciplinary) / Splicing Factor U2AF - genetics / Treatment Outcome / Tumor Suppressor Protein p53 - genetics / Whole Exome Sequencing