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

Autor:	Escherich CS; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.; Department for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany., Chen W; Department of Pathology, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Li Y; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN., Yang W; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN., Nishii R; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN., Li Z; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN., Raetz EA; Department of Pediatrics and Perlmutter Cancer Center, New York University Langone Health, New York, NY., Devidas M; Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN., Wu G; Department of Pathology, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Nichols KE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Inaba H; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Pui CH; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Jeha S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Camitta BM; Department of Pediatrics, Midwest Center for Cancer and Blood Disorders, Medical College of Wisconsin, Milwaukee, WI., Larsen E; Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME., Hunger SP; Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Loh ML; Department of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, University of Washington, Seattle, WA., Yang JJ; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 May 30; Vol. 143 (22), pp. 2270-2283.
DOI:	10.1182/blood.2023023336
Abstrakt:	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. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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