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Title: Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
Authors: Yoshizato, Tetsuichi
Dumitriu, Bogdan
Hosokawa, Kohei
Makishima, Hideki  kyouindb  KAKEN_id  orcid (unconfirmed)
Yoshida, Kenichi
Townsley, Danielle
Sato-Otsubo, Aiko
Sato, Yusuke
Liu, Delong
Suzuki, Hiromichi
Wu, Colin O
Shiraishi, Yuichi
Clemente, Michael J
Kataoka, Keisuke  kyouindb  KAKEN_id  orcid (unconfirmed)
Shiozawa, Yusuke
Okuno, Yusuke
Chiba, Kenichi
Tanaka, Hiroko
Nagata, Yasunobu
Katagiri, Takamasa
Kon, Ayana  kyouindb  KAKEN_id  orcid (unconfirmed)
Sanada, Masashi
Scheinberg, Phillip
Miyano, Satoru
Maciejewski, Jaroslaw P
Nakao, Shinji
Young, Neal S
Ogawa, Seishi  kyouindb  KAKEN_id
Author's alias: 吉里, 哲一
牧島, 秀樹
宮野, 悟
中尾, 眞二
小川, 誠司
Issue Date: 2-Jul-2015
Publisher: Massachusetts Medical Society
Journal title: The New England journal of medicine
Volume: 373
Issue: 1
Start page: 35
End page: 47
Abstract: [BACKGROUND]In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. [METHODS]We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. [RESULTS]Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- andBCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. [CONCLUSIONS]Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.)
Description: 再生不良性貧血における遺伝子変異の解明 -白血病発症にいたる過程を初めて解明-. 京都大学プレスリリース. 2015-07-09.
Rights: From [The New England journal of medicine, Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia, Volume 373, Page 35-47. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission.
DOI(Published Version): 10.1056/NEJMoa1414799
PubMed ID: 26132940
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