TY - JOUR
T1 - NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
AU - Belhadj, Sami
AU - Khurram, Aliya
AU - Bandlamudi, Chaitanya
AU - Palou-Márquez, Guillermo
AU - Ravichandran, Vignesh
AU - Steinsnyder, Zoe
AU - Wildman, Temima
AU - Catchings, Amanda
AU - Kemel, Yelena
AU - Mukherjee, Semanti
AU - Fesko, Benjamin
AU - Arora, Kanika
AU - Mehine, Miika
AU - Dandiker, Sita
AU - Izhar, Aalin
AU - Petrini, John
AU - Domchek, Susan
AU - Nathanson, Katherine L.
AU - Brower, Jamie
AU - Couch, Fergus
AU - Stadler, Zsofia
AU - Robson, Mark
AU - Walsh, Michael
AU - Vijai, Joseph
AU - Berger, Michael
AU - Supek, Fran
AU - Karam, Rachid
AU - Topka, Sabine
AU - Offit, Kenneth
N1 - Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2023/1/15
Y1 - 2023/1/15
N2 - 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 g-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.
AB - 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 g-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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U2 - 10.1158/1078-0432.CCR-22-1703
DO - 10.1158/1078-0432.CCR-22-1703
M3 - Article
C2 - 36346689
AN - SCOPUS:85146365313
SN - 1078-0432
VL - 29
SP - 422
EP - 431
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -