Login / Signup

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

Masanori YoshidaKazuhiko NakabayashiWentao YangAiko Sato-OtsuboShin-Ichi TsujimotoHiroko Ogata-KawataTomoko KawaiKeisuke IshiwataMika SakamotoKohji OkamuraKaoru YoshidaRyota ShiraiTomoo OsumiTakaya MoriyamaRina NishiiHiroyuki TakahashiChikako KiyotaniYoko ShiodaKeita TerashimaSae IshimaruYuki YuzaMasatoshi TakagiYuki ArakawaAkitoshi KinoshitaMoeko HinoToshihiko ImamuraDaisuke HasegawaYozo NakazawaMayuko OkuyaHarumi KakudaNao TakasugiAkiko InoueKentaro OhkiTakako YoshiokaShuichi ItoMasanori YoshidaKatsuyoshi KohKimikazu MatsumotoMasashi SanadaNobutaka KiyokawaAkira OharaSeishi OgawaAtsushi ManabeAkira NiwaKenichiro HataJun J YangMotohiro Kato
Published in: Blood advances (2021)
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. As 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 SMN (n = 14, 42.9%) than general population in gnomAD database (19.7%) (p = 0.042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMN was significantly higher among cases with NUDT15 variant (3.0%, 95% CI, 0.6%-9.4%) than those without (0.3%, 95% CI, 0.0-1.5%) (p = 0.045). The 6-MP dose of SMN patients with a NUDT15 variant was higher than that of those without SMN (p = 0.045). The 6-MP related mutational signature was observed in SMN specimens after 6-MP exposure. In cells under 6-MP exposure, a higher level of 6-MP-induced DNA damage in NUDT15 knockdown iPS cells. Our study indicates that NUDT15 variants may confer a risk of SMN after treatment with 6-MP among patients with ALL.
Keyphrases