Journal
BLOOD ADVANCES
Volume 5, Issue 23, Pages 5420-5428Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2021005507
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Funding
- Japan Society for the Promotion of Science [19K22608, 16K10026]
- Japan Agency for Medical Research and Development [JP20ck0106467, JP20kk0305014]
- National Center for Child Health and Development of Japan [2020A-1, 2019A-4]
- US National Institutes of Health [R01GM118578, R35GM141947]
- Grants-in-Aid for Scientific Research [19K22608, 16K10026] Funding Source: KAKEN
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The study identified a higher prevalence of NUDT15 hypomorphic variants in patients with SMNs after childhood leukemia/lymphoma, indicating a potential risk factor for SMNs in ALL patients treated with 6-MP. Additionally, the study found that NUDT15 variant carriers had higher cumulative incidence of SMNs and received higher doses of 6-MP compared to non-variant carriers. Furthermore, 6-MP exposure induced DNA damage in NUDT15-knockdown induced pluripotent stem cells, suggesting a mechanistic link between NUDT15 variants and SMNs development.
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.
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