NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response
Sami Belhadj1,2,3, Aliya Khurram1, Chaitanya Bandlamudi4
1Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
Purpose:
To explore the role of NBN as a pan-cancer susceptibility gene.
Experimental Design:
Matched 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.
Results:
We 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.
Conclusions:
Burden 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.
Insights
NBN gene variants increase cancer risk across multiple tumor types. Functional studies show these variants impair DNA repair, supporting NBN
Area of Science:
- Genetics
- Cancer Biology
- Genomic Medicine
Background:
- The NBN gene plays a crucial role in DNA double-strand break repair.
- Germline mutations in DNA repair genes are associated with hereditary cancer syndromes.
- Understanding NBN's role in cancer susceptibility is essential for risk assessment and targeted therapies.
Purpose of the Study:
- To investigate the role of the NBN gene as a pan-cancer susceptibility gene.
- To identify and characterize presumed pathogenic germline variants (PGVs) in NBN across diverse cancer types.
- To evaluate the functional consequences of NBN PGVs in cellular models.
Main Methods:
- Sequencing of germline and somatic DNA from over 34,000 cancer patients.
- Identification and analysis of presumed pathogenic germline variants (PGVs) in NBN.
- Case-control association studies and functional assays using cellular models.
- Analysis of protein expression, MRN complex formation, and response to gamma irradiation.
Main Results:
- Identified 83 carriers of 32 NBN PGVs (0.25% of patients), including the Slavic founder variant p.K219fs.
- NBN PGV carriers showed increased loss of the wild-type allele in tumors (OR=2.7, P=0.0024).
- Functional studies revealed novel NBN variants producing fragments that maintain MRE11 binding, leading to increased sensitivity to gamma irradiation.
Conclusions:
- Evidence supports NBN's role in a broad spectrum of cancers.
- Biallelic inactivation and functional data highlight NBN's contribution to cancer development.
- Further research in large pan-cancer cohorts is needed to fully define NBN's associations and interactions.
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