Data from <i>NBN</i> Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and <i>In Vitro</i> DNA Damage Response Defects

• DOI: 10.1158/1078-0432.c.6532968.v1
• Publication Date: 2023-04-01T05:57:26Z
• Authors: Sami Belhadj; Aliya Khurram; Chaitanya Bandlamudi; Guillermo Palou-M...; 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. Nath...; Jamie Brower; Fergus Couch; Zsofia Stadler; Mark Robson; Michael Walsh; Joseph Vijai; Michael Berger; Fran Supek; Rachid Karam; Sabine Topka; Kenneth Offit

&lt;div&gt;AbstractPurpose:&lt;p&gt;To explore the role of &lt;i&gt;NBN&lt;/i&gt; as a pan-cancer susceptibility gene.&lt;/p&gt;Experimental Design:&lt;p&gt;Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling Actionable Cancer Targets presumed pathogenic variants (PGV) identified. Allele-specific gene-centered analysis enrichment was conducted validation cohort 26,407 analyzed. Functional studies utilized cellular models with protein expression, MRN complex formation/localization, viability assessment following treatment γ-irradiation.&lt;/p&gt;Results:&lt;p&gt;We identified 83 carriers 32 PGVs (0.25% studied series), 40% which (33/83) carried Slavic founder p.K219fs. The frequency varied across cancer types. Patients harboring demonstrated increased loss wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; &lt;i&gt;P&lt;/i&gt; 0.0024; pan-cancer], including lung pancreatic compared breast colorectal cancers. p.K219fs enriched all tumor types (OR 2.22; CI: 1.3–3.6; 0.0018). Gene-centered revealed cases controls European population 1.9; 1.3–2.7; 0.0004), finding confirmed replication 1.8; 1.2–2.6; 0.003). Two novel truncating variants, p.L19* p.N71fs, produced 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity γ-irradiation lower levels radiation-induced KAP1 phosphorylation.&lt;/p&gt;Conclusions:&lt;p&gt;Burden analyses, biallelic inactivation, functional evidence support contributing broad spectrum. Further large series epistatic environmental interactions are warranted further define associations.&lt;/p&gt;&lt;/div&gt;