American Association for Cancer Research
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Figure S4 from NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects

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posted on 2023-04-01, 00:08 authored by Sami Belhadj, Aliya Khurram, Chaitanya Bandlamudi, Guillermo Palou-Márquez, Vignesh Ravichandran, Zoe Steinsnyder, Temima Wildman, Amanda Catchings, Yelena Kemel, Semanti Mukherjee, Benjamin Fesko, Kanika Arora, Miika Mehine, Sita Dandiker, Aalin Izhar, John Petrini, Susan Domchek, Katherine L. Nathanson, Jamie Brower, Fergus Couch, Zsofia Stadler, Mark Robson, Michael Walsh, Joseph Vijai, Michael Berger, Fran Supek, Rachid Karam, Sabine Topka, Kenneth Offit

Supplementary Figure S4. Alternative somatic second hit analysis.


National Cancer Institute (NCI)

United States Department of Health and Human Services

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