NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia-Reference-Cited by-同舟云学术

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

Published:2021-12-13 Issue:23 Volume:5 Page:5420-5428
ISSN:2473-9529
Container-title:Blood Advances
language:en
Short-container-title:

Author:

Yoshida Masanori¹²^ORCID,Nakabayashi Kazuhiko³,Yang Wentao⁴,Sato-Otsubo Aiko¹⁵,Tsujimoto Shin-ichi¹²^ORCID,Ogata-Kawata Hiroko³^ORCID,Kawai Tomoko³^ORCID,Ishiwata Keisuke³,Sakamoto Mika⁶,Okamura Kohji⁷^ORCID,Yoshida Kaoru¹,Shirai Ryota¹²^ORCID,Osumi Tomoo¹⁸^ORCID,Moriyama Takaya⁴,Nishii Rina⁴,Takahashi Hiroyuki⁹^ORCID,Kiyotani Chikako⁸,Shioda Yoko⁸,Terashima Keita⁸,Ishimaru Sae¹⁰,Yuza Yuki¹⁰,Takagi Masatoshi¹¹,Arakawa Yuki¹²^ORCID,Kinoshita Akitoshi¹³,Hino Moeko¹⁴,Imamura Toshihiko¹⁵,Hasegawa Daisuke¹⁶,Nakazawa Yozo¹⁷^ORCID,Okuya Mayuko¹⁸,Kakuda Harumi¹⁹,Takasugi Nao⁵,Inoue Akiko²⁰^ORCID,Ohki Kentaro¹,Yoshioka Takako²¹,Ito Shuichi²^ORCID,Tomizawa Daisuke⁸^ORCID,Koh Katsuyoshi¹²,Matsumoto Kimikazu⁸^ORCID,Sanada Masashi²²,Kiyokawa Nobutaka¹,Ohara Akira⁹,Ogawa Seishi²³^ORCID,Manabe Atsushi²⁴,Niwa Akira²⁵^ORCID,Hata Kenichiro³^ORCID,Yang Jun J.²⁶⁴,Kato Motohiro¹⁸^ORCID

Affiliation:

1. Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan;

2. Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan;

3. Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Tokyo, Japan;

4. Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA;

5. Department of Pediatrics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan;

6. Medical Genome Center, Research Institute, National Center for Child Health and Development, Tokyo, Japan;

7. Department of Systems BioMedicine, Research Institute, National Center for Child Health and Development, Tokyo, Japan;

8. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;

9. Department of Pediatrics, Toho University, Tokyo, Japan;

10. Department of Hematology/Oncology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan;

11. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;

12. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan;

13. Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan;

14. Department of Pediatrics, Chiba University Hospital, Chiba, Japan;

15. Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan;

16. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan;

17. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan;

18. Department of Pediatrics, Dokkyo Medical University School of Medicine, Shimotsuga, Japan;

19. Department of Hematology/Oncology, Chiba Children’s Hospital, Chiba, Japan;

20. Department of Pediatrics, Osaka Medical and Pharmaceutical University, Takatsuki, Japan;

21. Department of Pathology, National Center for Child Health and Development, Tokyo, Japan;

22. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan;

23. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;

24. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan;

25. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; and

26. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Hematology

Link

https://ashpublications.org/bloodadvances/article-pdf/5/23/5420/1851209/advancesadv2021005507.pdf

Reference30 articles.

1. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia;Hijiya;JAMA.,2007

2. Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study;Sacchi;Haematologica.,2008

3. Risk of subsequent neoplasms during the fifth and sixth decades of life in the Childhood Cancer Survivor Study cohort [published correction appears in J Clin Oncol. 2018;36(8):833-834];Turcotte;J Clin Oncol.,2015

4. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study;Friedman;J Natl Cancer Inst.,2010

5. Chemotherapy and risk of subsequent malignant neoplasms in the Childhood Cancer Survivor Study cohort;Turcotte;J Clin Oncol.,2019

Cited by 4 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Prevalence of pathogenic variants in cancer‐predisposing genes in second cancer after childhood solid cancers;Cancer Medicine;2023-04-06

2. The heterozygous NUDT15 variant is not associated with the severity of 6-mercaptopurine-related side effects in early intensification therapy for childhood acute lymphoblastic leukemia;EJC Paediatric Oncology;2023

3. Recent progress in pediatric lymphoblastic leukemia;International Journal of Hematology;2022-12-01

4. A Case of Gorlin-Goltz Syndrome Without the Characteristic Physical Features That Was Diagnosed After the Development of a Fifth Cancer;Journal of Pediatric Hematology/Oncology;2022-03-01