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

Masanori Yoshida, Kazuhiko Nakabayashi, Wentao Yang, Aiko Sato-Otsubo, Shin Ichi Tsujimoto, Hiroko Ogata-Kawata, Tomoko Kawai, Keisuke Ishiwata, Mika Sakamoto, Kohji Okamura, Kaoru Yoshida, Ryota Shirai, Tomoo Osumi, Takaya Moriyama, Rina Nishii, Hiroyuki Takahashi, Chikako Kiyotani, Yoko Shioda, Keita Terashima, Sae IshimaruYuki Yuza, Masatoshi Takagi, Yuki Arakawa, Akitoshi Kinoshita, Moeko Hino, Toshihiko Imamura, Daisuke Hasegawa, Yozo Nakazawa, Mayuko Okuya, Harumi Kakuda, Nao Takasugi, Akiko Inoue, Kentaro Ohki, Takako Yoshioka, Shuichi Ito, Daisuke Tomizawa, Katsuyoshi Koh, Kimikazu Matsumoto, Masashi Sanada, Nobutaka Kiyokawa, Akira Ohara, Seishi Ogawa, Atsushi Manabe, Akira Niwa, Kenichiro Hata, Jun J. Yang, Motohiro Kato

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

2 Citaten (Scopus)

Samenvatting

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 5 14; 42.9%) than in the general population in the gnomAD database (19.7%; P 5 .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 5 .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P 5 .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.

Originele taal-2Engels
Pagina's (van-tot)5420-5428
Aantal pagina's9
TijdschriftBlood Advances
Volume5
Nummer van het tijdschrift23
DOI's
StatusGepubliceerd - 14 dec. 2021
Extern gepubliceerdJa

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