ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Germ line genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children.Blood · 2024Trial
- Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions.European journal of human genetics : EJHG · 2026Review
- Molecular landscape and clinical translation of DNA damage response alterations in solid tumors: A pan-cancer perspective on precision oncology.Neoplasia (New York, N.Y.) · 2026Review
- Double jeopardy: howFrontiers in cell and developmental biology · 2026Review
- Functional phosphoproteomic analysis of SMG1 in nonsense-mediated mRNA decay and DNA damage repair in cancer.Frontiers in systems biology · 2026Article
- Review
- Improving Global Access to Genomic Profiling in Rare Pediatric Cancers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.Nature genetics · 2025Article
- Moderate-Low Risk Breast Cancer Gene Expression in a Romanian Population.International journal of molecular sciences · 2025Article
- Germline Genetic Testing in Patients with Bone and Soft Tissue Sarcoma: A Prospective Multicenter Study to Evaluate Cancer Susceptibility.International journal of molecular sciences · 2025Article
- An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene.Acta neuropathologica communications · 2025Article
- Bioinformatics Based Drug Repurposing Approach for Breast and Gynecological Cancers:European journal of breast health · 2025Article
- Post-therapy emergence of an NBN reversion mutation in a patient with pancreatic acinar cell carcinoma.NPJ precision oncology · 2024Article
- Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery.Biomedicines · 2024Review
Corrections and comments
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Authors and funding
29 authors at 6 institutions in 2 countries.
Funding
Abstract
purposeTo explore the role of NBN as a pan-cancer susceptibility gene. EXPERIMENTAL
designMatched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation.
resultsWe identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4-5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3-3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3-2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2-2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation.
conclusionsBurden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.
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