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Germ line genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children

Escherich, Carolin S., Chen, Wenan, Li, Yizhen, Yang, Wenjian, Nishii, Rina, Li, Zhenhua, Raetz, Elizabeth A., Devidas, Meenakshi, Wu, Gang, Nichols, Kim E., Inaba, Hiroto, Pui, Ching-Hon, Jeha, Sima, Camitta, Bruce M., Larsen, Eric, Hunger, Stephen P., Loh, Mignon L., Yang, Jun J.·2024·Blood
DOI 10.1182/blood.2023023336
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Abstract

Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen breakage syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germ line NBN variants may also be at risk for leukemia development, although this is much less characterized. By sequencing 4325 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), we systematically examined the frequency of germ line NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD noncancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118 479 individuals), we found significant overrepresentation in pediatric B-ALL (P = .004; odds ratio, 1.8). Most B-ALL–risk variants were missense and cluster within the NBN N-terminal domains. Using 2 functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as nonfunctional or partially functional. Finally, we found that germ line NBN variant carriers, all of whom were identified as heterozygous genotypes, showed similar survival outcomes relative to those with wild type status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy. These trials were registered at www.clinicaltrials.gov as #NCT01225874, NCT00075725, NCT00103285, NCI-T93-0101D, and NCT00137111.

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Crossref · 10.1182/blood.2023023336

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Figure 1 Workflow for NBNtargeted sequencing in pediatric B-ALL patients.
Figure 1 Workflow for NBNtargeted sequencing in pediatric B-ALL patients.CC-BY · From the PDF
Figure 2 Experimental design for NBN variant functional characterization.
Figure 2 Experimental design for NBN variant functional characterization.CC-BY · From the PDF
Figure 3
Figure 3 CC-BY · From the PDF
Figure 4 NBN variant mitomycin C drug sensitivity screen.
Figure 4 NBN variant mitomycin C drug sensitivity screen.CC-BY · From the PDF
Figure 5 Key functional domains of NBN are preferentially affected by genetic variation.
Figure 5 Key functional domains of NBN are preferentially affected by genetic variation.CC-BY · From the PDF
Image 6
CC-BY · From the PDF

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Cited by

Metadata

Authors
Escherich, C. S., Chen, W., Li, Y., Yang, W., Nishii, R., Li, Z., Raetz, E. A., Devidas, M., Wu, G., Nichols, K. E., Inaba, H., Pui, C.-H., Jeha, S., Camitta, B. M., Larsen, E., Hunger, S. P., Loh, M. L., & Yang, J. J.
Venue
Blood
Publisher
American Society of Hematology
Published
2024-05-30
Volume
143
Issue
22
Pages
2270-2283
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood.2023023336
Cited by
17
References
2
Language
en

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