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 = 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.

Prevalence of pathogenic variants in cancer‐predisposing genes in second cancer after childhood solid cancers

“…Complete methods of sample preparation and WES are shown in detail in the Supplementary files. The selection of the CPG genes and the evaluation of the pathogenicity were performed as previously reported 15 . In brief, variants of 162 known CPGs (Table S2) listed in previous reports 9,16 were extracted from each sample.…”

“…To investigate the etiology of SMN development, mutational signature analysis was performed using a previously described method 15 . Known mutational signatures were obtained from the COSMIC database (Mutational signatures V3, http://synapse.org ID: syn12009743) and from Li et al 19 …”

“…The selection of the CPG genes and the evaluation of the pathogenicity were performed as previously reported. 15 In brief, variants of 162 known CPGs (Table S2 ) listed in previous reports 9 , 16 were extracted from each sample. Then, the pathogenicity of each variant was manually evaluated using online databases and the guideline of the American College of Medical Genetics and Genomics 17 (detailed in the Supplementary methods).…”

A Case of Gorlin-Goltz Syndrome Without the Characteristic Physical Features That Was Diagnosed After the Development of a Fifth Cancer

“…We conducted whole exome sequencing, while focusing especially on potential pathogenic variants in cancer predisposing genes in nail and oral mucosa samples as similar with previously described methods. 5 Owing to the low frequency of frameshift mutations in the PTCH1 gene (exon10: c.1350delC: p. L450fs) in the oral mucosa, samples of basal cell carcinoma and normal skin were re-examined by using the Sanger method. The sequence of PTCH1 is shown in Figure (Supplemental Digital Content 2, http://links.lww.com/JPHO/A514).…”

Recent progress in pediatric lymphoblastic leukemia

“…The NUDT15 polymorphism is more common in Asians, and upfront genotyping is useful to reduce the risk of severe myelosuppression and interruption of maintenance therapy [26]. Furthermore, the incidence of secondary cancers is high among carriers of this NUDT15 variant because of the enhanced DNA damage caused by its high sensitivity to 6-MP [27].…”