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Myelodysplastic Syndromes
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):358-365
Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki
Masataka Taguchi,1 Hiroyuki Mishima,2 Yusuke Shiozawa,3 Chisa Hayashida,2 Akira Kinoshita,2 Yasuhito Nannya,3 Hideki Makishima,3 Makiko Horai,1 Masatoshi Matsuo,1 Shinya Sato,1 Hidehiro Itonaga,1 Takeharu Kato,1
Hiroaki Taniguchi,4 Daisuke Imanishi,1 Yoshitaka Imaizumi,1 Tomoko Hata,1 Motoi Takenaka,5 Yukiyoshi Moriuchi,4 Yuichi Shiraishi,6 Satoru Miyano,6,7 Seishi Ogawa,3 Koh-ichiro Yoshiura2 and Yasushi Miyazaki1
1Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 2Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 3Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; 4Department of Hematology, Sasebo City General Hospital, Sasebo; 5Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 6Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo and 7Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
ABSTRACT
Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chro- mosomes 3, 8, and 11. However, there was no difference in the median sur- vival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that prox- imally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration pro- files in MDS among atomic bomb survivors differed from those in therapy- related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure.
Introduction
Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by cytopenias related to ineffective hematopoiesis, dysplasia, and progression to acute myeloid leukemia.1 The pathogenesis of MDS is not yet fully understood; however, recently developed DNA sequencing technologies have clearly demonstrated the important roles of genome alterations. The most frequent mutations observed in de novo MDS are in the genes coding splicing factors (e.g. SF3B1 and SRSF2), fol- lowed by mutations in the genes for DNA methylation (e.g. TET2 and DNMT3A) and histone modification (e.g. ASXL1 and EZH2).2-4 Typically, these somatic muta-
Correspondence:
YASUSHI MIYAZAKI
y-miyaza@nagasaki-u.ac.jp
Received: February 12, 2019. Accepted: May 16, 2019. Pre-published: May 17, 2019.
doi:10.3324/haematol.2019.219386
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