> Details

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; [...]

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

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
  • Contributor: 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; [...]
  • imprint: American Association for Cancer Research (AACR), 2023
  • Published in: Clinical Cancer Research
  • Language: English
  • DOI: 10.1158/1078-0432.ccr-22-1703
  • ISSN: 1557-3265; 1078-0432
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>To explore the role of NBN as a pan-cancer susceptibility gene.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
  • Access State: Open Access