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NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects.

PURPOSE
To explore the role of NBN as a pan-cancer susceptibility gene.


METHODS
Matched germline and somatic DNA samples from 34,046 patients were sequenced using MSK-IMPACT and presumed pathogenic germline variants (PGVs) 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, CI:1.4-5.5 p=0.0024; pan-cancer), including lung and pancreatic tumors compared to 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 to 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 45kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to g-irradiation and lower levels of radiation-induced KAP1 phosphorylation.


CONCLUSION
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.