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NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects

Belhadj, Sami, Khurram, Aliya, Bandlamudi, Chaitanya, Palou-Márquez, Guillermo, Ravichandran, Vignesh, Steinsnyder, Zoe, Wildman, Temima, Catchings, Amanda, Kemel, Yelena, Mukherjee, Semanti, Fesko, Benjamin, Arora, Kanika, Mehine, Miika, Dandiker, Sita, Izhar, Aalin, Petrini, John, Domchek, Susan, Nathanson, Katherine L., Brower, Jamie, Couch, Fergus, Stadler, Zsofia, Robson, Mark, Walsh, Michael, Vijai, Joseph, Berger, Michael, Supek, Fran, Karam, Rachid, Topka, Sabine, Offit, Kenneth·2023·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-22-1703PMC PMC9843434

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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.

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Metadata

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.
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2022-11-08
Volume
29
Issue
2
Pages
422-431
ISSN
  • 1078-0432
  • 1557-3265
DOI
10.1158/1078-0432.ccr-22-1703
PMC
PMC9843434
Cited by
24
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 70 d)
Funders
National Cancer Institute (P30 CA008748, 1R01 CA217169, 1R01 CA234617)

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