FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4385667773> ?p ?o ?g. }

• W4385667773 endingPage "e4470514" @default.
• W4385667773 startingPage "e4470514" @default.
• W4385667773 abstract "Background: Nibrin, encoded by the NBN gene, is involved in cellular DNA damage response. In complex with MRE11 and RAD50, nibrin recognizes DNA double-stranded breaks and facilitates downstream signaling cascades. The homozygous loss-of-function (LoF) variant p.K291fs in the NBN gene is associated with the Nijmegen Breakage Syndrome, an autosomal recessive syndrome related to cancer predisposition. Carriers of a heterozygous NBN germline variant also have a higher propensity to develop cancer, although this is much less characterized. Aims: We sought to evaluate the pattern and prevalence of NBN germline variants in pediatric B-ALL. Furthermore, we aim to functionally characterize individual NBN variants, most of which are currently classified as uncertain significance. Methods: First, we performed targeted sequencing of coding regions of the NBN gene in 4,183 children with newly diagnosed B-ALL enrolled in Children’s Oncology Group (COG) clinical trials (AALL0232, P9900, and AALL0331) and St. Jude Total XIII and XV clinical trials. Rare-variant burden test was performed using the CoCoRV pipeline (Chen W. et al., Nat Commun. 2022, PMID: 35545612), with the gnomAD v2.1 exome-based non-cancer summary counts (n=118,479) used as non-ALL controls. Rare deleterious NBN variants were defined as (1) a population allele frequency ≤1x10-3 in gnomAD and (2) a Combined Annotation Dependent Depletion (CADD) score >20. NBN variants identified in this cohort were subjected to two types of phenotyping to determine their functional consequences on (1) NBN protein stability and (2) Mitomycin C drug sensitivity. Functional screening was implemented using the HEK293T landing pad cell line (Matreyek K. et al., Nucleic Acids Res. 2020, PMID: 31612958). Finally, we compared the clinical characteristics and treatment outcome of B-ALL patients with LoF NBN germline variant (n=29) and B-ALL patients with NBN wild-type (WT) status (n=4,309). Results: Overall, we identified 25 unique rare and predicted deleterious NBN coding variants in 50 B-ALL patients. Three variants resulted in protein truncation, including the known LoF variant, p.K219fs. The remaining 22 missense variants clustered in the N-terminal domains, and all but one are classified as uncertain significance. Examining the burden of rare variants in B-ALL cases vs. gnomAD controls, we found a significant enrichment of predicted deleterious NBN variants in B-ALL patients (p=0.025, OR=1.6). The association with ALL risk was particularly strong when we restricted the analyses to variants affecting the BRCT2 domain (p=0.005, OR=2.5). Testing these NBN variants for their effects on nibrin stability, we identified 13 that resulted in highly unstable protein, defined as >50% reduction compared with WT protein. Of those, seven variants also showed a particular high sensitivity to DNA damage by Mitomycin C. Finally, we analyzed the clinical features of B-ALL patients with experimentally validated LoF NBN variants by comparing them with B-ALL patients and NBN WT status. We did not observe significant differences in age, gender, ancestry, or leukemia subtype. Also, treatment related adverse events did not differ between NBN variant carriers and those without. Summary/Conclusion: We systematically examined germline genetic variants in the NBN gene in B-ALL patients, reporting 25 rare deleterious NBN variants with a cumulative frequency of 1.2%. We experimentally identified a series of LoF variants beyond the known p.K291fs variant. Taken together, our findings provide novel insights into the genetic predisposition to pediatric B-ALL and the impact of NBN variants on nibrin function.Keywords: Pediatric, B cell acute lymphoblastic leukemia, DNA damage" @default.
• W4385667773 created "2023-08-09" @default.
• W4385667773 creator A5010840699 @default.
• W4385667773 creator A5018363328 @default.
• W4385667773 creator A5021280754 @default.
• W4385667773 creator A5023214494 @default.
• W4385667773 creator A5024573751 @default.
• W4385667773 creator A5025442855 @default.
• W4385667773 creator A5028647628 @default.
• W4385667773 creator A5030319840 @default.
• W4385667773 creator A5035759509 @default.
• W4385667773 creator A5044030725 @default.
• W4385667773 creator A5057538695 @default.
• W4385667773 creator A5059960472 @default.
• W4385667773 creator A5075936752 @default.
• W4385667773 creator A5085010022 @default.
• W4385667773 date "2023-08-01" @default.
• W4385667773 modified "2023-09-27" @default.
• W4385667773 title "S107: IDENTIFICATION AND CHARACTERIZATION OF GERMLINE NBN VARIANTS RELATED TO B-ALL PREDISPOSITION" @default.
• W4385667773 doi "https://doi.org/10.1097/01.hs9.0000967340.44705.14" @default.
• W4385667773 hasPublicationYear "2023" @default.
• W4385667773 type Work @default.
• W4385667773 citedByCount "0" @default.
• W4385667773 crossrefType "journal-article" @default.
• W4385667773 hasAuthorship W4385667773A5010840699 @default.
• W4385667773 hasAuthorship W4385667773A5018363328 @default.
• W4385667773 hasAuthorship W4385667773A5021280754 @default.
• W4385667773 hasAuthorship W4385667773A5023214494 @default.
• W4385667773 hasAuthorship W4385667773A5024573751 @default.
• W4385667773 hasAuthorship W4385667773A5025442855 @default.
• W4385667773 hasAuthorship W4385667773A5028647628 @default.
• W4385667773 hasAuthorship W4385667773A5030319840 @default.
• W4385667773 hasAuthorship W4385667773A5035759509 @default.
• W4385667773 hasAuthorship W4385667773A5044030725 @default.
• W4385667773 hasAuthorship W4385667773A5057538695 @default.
• W4385667773 hasAuthorship W4385667773A5059960472 @default.
• W4385667773 hasAuthorship W4385667773A5075936752 @default.
• W4385667773 hasAuthorship W4385667773A5085010022 @default.
• W4385667773 hasBestOaLocation W43856677731 @default.
• W4385667773 hasConcept C104317684 @default.
• W4385667773 hasConcept C10590036 @default.
• W4385667773 hasConcept C109825262 @default.
• W4385667773 hasConcept C143425029 @default.
• W4385667773 hasConcept C16671776 @default.
• W4385667773 hasConcept C180754005 @default.
• W4385667773 hasConcept C2777136964 @default.
• W4385667773 hasConcept C2779486608 @default.
• W4385667773 hasConcept C2908647359 @default.
• W4385667773 hasConcept C501734568 @default.
• W4385667773 hasConcept C54355233 @default.
• W4385667773 hasConcept C552990157 @default.
• W4385667773 hasConcept C71924100 @default.
• W4385667773 hasConcept C86803240 @default.
• W4385667773 hasConcept C99454951 @default.
• W4385667773 hasConceptScore W4385667773C104317684 @default.
• W4385667773 hasConceptScore W4385667773C10590036 @default.
• W4385667773 hasConceptScore W4385667773C109825262 @default.
• W4385667773 hasConceptScore W4385667773C143425029 @default.
• W4385667773 hasConceptScore W4385667773C16671776 @default.
• W4385667773 hasConceptScore W4385667773C180754005 @default.
• W4385667773 hasConceptScore W4385667773C2777136964 @default.
• W4385667773 hasConceptScore W4385667773C2779486608 @default.
• W4385667773 hasConceptScore W4385667773C2908647359 @default.
• W4385667773 hasConceptScore W4385667773C501734568 @default.
• W4385667773 hasConceptScore W4385667773C54355233 @default.
• W4385667773 hasConceptScore W4385667773C552990157 @default.
• W4385667773 hasConceptScore W4385667773C71924100 @default.
• W4385667773 hasConceptScore W4385667773C86803240 @default.
• W4385667773 hasConceptScore W4385667773C99454951 @default.
• W4385667773 hasIssue "S3" @default.
• W4385667773 hasLocation W43856677731 @default.
• W4385667773 hasLocation W43856677732 @default.
• W4385667773 hasOpenAccess W4385667773 @default.
• W4385667773 hasPrimaryLocation W43856677731 @default.
• W4385667773 hasRelatedWork W1906082248 @default.
• W4385667773 hasRelatedWork W1970327593 @default.
• W4385667773 hasRelatedWork W1988517967 @default.
• W4385667773 hasRelatedWork W1995692004 @default.
• W4385667773 hasRelatedWork W2057739827 @default.
• W4385667773 hasRelatedWork W2070922469 @default.
• W4385667773 hasRelatedWork W2117897636 @default.
• W4385667773 hasRelatedWork W2159173718 @default.
• W4385667773 hasRelatedWork W2223919059 @default.
• W4385667773 hasRelatedWork W3165452661 @default.
• W4385667773 hasVolume "7" @default.
• W4385667773 isParatext "false" @default.
• W4385667773 isRetracted "false" @default.
• W4385667773 workType "article" @default.