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 Ishimaru; Yuki 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

doi:10.1182/bloodadvances.2021005507

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

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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-2	Engels
Pagina's (van-tot)	5420-5428
Aantal pagina's	9
Tijdschrift	Blood Advances
Volume	5
Nummer van het tijdschrift	23
DOI's	https://doi.org/10.1182/bloodadvances.2021005507
Status	Gepubliceerd - 14 dec. 2021
Extern gepubliceerd	Ja

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10.1182/bloodadvances.2021005507

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Yoshida, M., Nakabayashi, K., Yang, W., Sato-Otsubo, A., Tsujimoto, S. I., Ogata-Kawata, H., Kawai, T., Ishiwata, K., Sakamoto, M., Okamura, K., Yoshida, K., Shirai, R., Osumi, T., Moriyama, T., Nishii, R., Takahashi, H., Kiyotani, C., Shioda, Y., Terashima, K., ... Kato, M. (2021). NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia. Blood Advances, 5(23), 5420-5428. https://doi.org/10.1182/bloodadvances.2021005507

@article{ea974250b38e4ac0834f4b13bf46bea4,

title = "NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia",

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 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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 by The American Society of Hematology.",

year = "2021",

month = dec,

day = "14",

doi = "10.1182/bloodadvances.2021005507",

language = "English",

volume = "5",

pages = "5420--5428",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "23",

}

Yoshida, M, Nakabayashi, K, Yang, W, Sato-Otsubo, A, Tsujimoto, SI, Ogata-Kawata, H, Kawai, T, Ishiwata, K, Sakamoto, M, Okamura, K, Yoshida, K, Shirai, R, Osumi, T, Moriyama, T, Nishii, R, Takahashi, H, Kiyotani, C, Shioda, Y, Terashima, K, Ishimaru, S, Yuza, Y, Takagi, M, Arakawa, Y, Kinoshita, A, Hino, M, Imamura, T, Hasegawa, D, Nakazawa, Y, Okuya, M, Kakuda, H, Takasugi, N, Inoue, A, Ohki, K, Yoshioka, T, Ito, S, Tomizawa, D, Koh, K, Matsumoto, K, Sanada, M, Kiyokawa, N, Ohara, A, Ogawa, S, Manabe, A, Niwa, A, Hata, K, Yang, JJ & Kato, M 2021, 'NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia', Blood Advances, vol. 5, nr. 23, blz. 5420-5428. https://doi.org/10.1182/bloodadvances.2021005507

TY - JOUR

T1 - NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

AU - Yoshida, Masanori

AU - Nakabayashi, Kazuhiko

AU - Yang, Wentao

AU - Sato-Otsubo, Aiko

AU - Tsujimoto, Shin Ichi

AU - Ogata-Kawata, Hiroko

AU - Kawai, Tomoko

AU - Ishiwata, Keisuke

AU - Sakamoto, Mika

AU - Okamura, Kohji

AU - Yoshida, Kaoru

AU - Shirai, Ryota

AU - Osumi, Tomoo

AU - Moriyama, Takaya

AU - Nishii, Rina

AU - Takahashi, Hiroyuki

AU - Kiyotani, Chikako

AU - Shioda, Yoko

AU - Terashima, Keita

AU - Ishimaru, Sae

AU - Yuza, Yuki

AU - Takagi, Masatoshi

AU - Arakawa, Yuki

AU - Kinoshita, Akitoshi

AU - Hino, Moeko

AU - Imamura, Toshihiko

AU - Hasegawa, Daisuke

AU - Nakazawa, Yozo

AU - Okuya, Mayuko

AU - Kakuda, Harumi

AU - Takasugi, Nao

AU - Inoue, Akiko

AU - Ohki, Kentaro

AU - Yoshioka, Takako

AU - Ito, Shuichi

AU - Tomizawa, Daisuke

AU - Koh, Katsuyoshi

AU - Matsumoto, Kimikazu

AU - Sanada, Masashi

AU - Kiyokawa, Nobutaka

AU - Ohara, Akira

AU - Ogawa, Seishi

AU - Manabe, Atsushi

AU - Niwa, Akira

AU - Hata, Kenichiro

AU - Yang, Jun J.

AU - Kato, Motohiro

PY - 2021/12/14

Y1 - 2021/12/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122150579&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2021005507

DO - 10.1182/bloodadvances.2021005507

M3 - Article

C2 - 34662904

AN - SCOPUS:85122150579

SN - 2473-9529

VL - 5

SP - 5420

EP - 5428

JO - Blood Advances

JF - Blood Advances

IS - 23

ER -

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

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