NUDT15 variants may confer a risk of second cancers after treatment with 6-MP among patients with acute lymphoblastic leukemia.
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.