<i>NUDT15</i> variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia
-
- Masanori Yoshida
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Wentao Yang
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA;
-
- Aiko Sato-Otsubo
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Shin-ichi Tsujimoto
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Hiroko Ogata-Kawata
- Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Tomoko Kawai
- Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Keisuke Ishiwata
- Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Mika Sakamoto
- Medical Genome Center, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Kohji Okamura
- Department of Systems BioMedicine, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Kaoru Yoshida
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Ryota Shirai
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Tomoo Osumi
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Takaya Moriyama
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA;
-
- Rina Nishii
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA;
-
- Hiroyuki Takahashi
- Department of Pediatrics, Toho University, Tokyo, Japan;
-
- Chikako Kiyotani
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
-
- Yoko Shioda
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
-
- Keita Terashima
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
-
- Sae Ishimaru
- Department of Hematology/Oncology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan;
-
- Yuki Yuza
- Department of Hematology/Oncology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan;
-
- Masatoshi Takagi
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
-
- Yuki Arakawa
- Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan;
-
- Akitoshi Kinoshita
- Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan;
-
- Moeko Hino
- Department of Pediatrics, Chiba University Hospital, Chiba, Japan;
-
- Toshihiko Imamura
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan;
-
- Daisuke Hasegawa
- Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan;
-
- Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan;
-
- Mayuko Okuya
- Department of Pediatrics, Dokkyo Medical University School of Medicine, Shimotsuga, Japan;
-
- Harumi Kakuda
- Department of Hematology/Oncology, Chiba Children’s Hospital, Chiba, Japan;
-
- Nao Takasugi
- Department of Pediatrics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan;
-
- Akiko Inoue
- Department of Pediatrics, Osaka Medical and Pharmaceutical University, Takatsuki, Japan;
-
- Kentaro Ohki
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan;
-
- Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan;
-
- Daisuke Tomizawa
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
-
- Katsuyoshi Koh
- Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan;
-
- Kimikazu Matsumoto
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
-
- Masashi Sanada
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan;
-
- Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Akira Ohara
- Department of Pediatrics, Toho University, Tokyo, Japan;
-
- Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
-
- Atsushi Manabe
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan;
-
- Akira Niwa
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; and
-
- Kenichiro Hata
- Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
-
- Jun J. Yang
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
-
- Motohiro Kato
- Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.</jats:p>
収録刊行物
-
- Blood Advances
-
Blood Advances 5 (23), 5420-5428, 2021-12-13
American Society of Hematology