NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects Journal Article
| Authors: | Belhadj, S.; Khurram, A.; Bandlamudi, C.; Palou-Márquez, G.; Ravichandran, V.; Steinsnyder, Z.; Wildman, T.; Catchings, A.; Kemel, Y.; Mukherjee, S.; Fesko, B.; Arora, K.; Mehine, M.; Dandiker, S.; Izhar, A.; Petrini, J.; Domchek, S.; Nathanson, K. L.; Brower, J.; Couch, F.; Stadler, Z.; Robson, M.; Walsh, M.; Vijai, J.; Berger, M.; Supek, F.; Karam, R.; Topka, S.; Offit, K. |
| Article Title: | NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects |
| Abstract: | 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. ©2022 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | genetics; mutation; pancreatic neoplasms; cell cycle protein; cell cycle proteins; dna damage; genetic predisposition to disease; nuclear protein; germ cell; pathology; nuclear proteins; germ cells; pancreas tumor; genetic predisposition; germ-line mutation; germline mutation; humans; human; nbn protein, human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 29 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-01-15 |
| Start Page: | 422 |
| End Page: | 431 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-1703 |
| PUBMED: | 36346689 |
| PROVIDER: | scopus |
| PMCID: | PMC9843434 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author's are MSK author: Sabine Topka and Kenneth Offit -- Source: Scopus |
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