Purpose: To explore the role of NBN as a pan-cancer susceptibility gene. Methods: Matched germline and somatic DNA samples from 34,046 patients were sequenced using MSK-IMPACT and presumed pathogenic germline variants (PGVs) 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, CI:1.4-5.5 p=0.0024; pan-cancer), including lung and pancreatic tumors compared to 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 to 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 45kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to g-irradiation and lower levels of radiation-induced KAP1 phosphorylation. Conclusion: 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.
The role of genetic testing in the practice of dermatology is expanding, yet obtaining coverage for genetic testing remains a challenge. We propose several solutions as to how this can be remedied.
2007 Background: NCCN now endorses BRCA founder mutation genetic testing (GT) via longitudinal studies in all Ashkenazi Jewish (AJ) individuals. The BRCA Founder OutReach (BFOR) study offers pre-GT online education with posttest engagement of primary care providers (PCPs). Methods: The study in 4 US cities enrolls those age > 25 with > 1 AJ grandparent. Participants enroll online with chatbot and video education, have GT at local centers, receive results from their PCP or BFOR staff, and are surveyed 12 weeks post disclosure and annually for 5 years. Univariate analyses and multivariable (MV) logistic regression models were used to evaluate characteristics associated with not completing GT, selecting PCP to disclose GT, and positive GT. Results: As of January 2020, 4754 participants consented (77.5% female, median age 51); 37.7% never previously considered GT. Cancer family histories (FHx) were 56.4% low risk (LR), 36.4% high risk (HR), and 7.2% had a familial mutation (FM). To date, 3658 participants (76.9%) completed and 677 (14.2%) did not complete GT; the remainder are pending. Only 34.8% of participants selected PCP to disclose GT, and 42.6% of PCPs agreed. Of the 124 mutation carriers (3.4%) identified, 60.5% had a FM. At the 12-week survey, 65.4% of mutation carriers planned to proceed with recommended screening or scheduled risk reducing surgery; 3.5% of those with negative GT and HR FHx reported further GT. Satisfaction was high (mean 9.58/10, SD 1.12) and unrelated to result (p>.05). Conclusions: A digital model for founder mutation testing engaged those with LR FHx and no prior experience with GT. Older participants were more likely to complete the study. Males were less likely to enroll but more likely to carry mutations. The majority of those who tested positive had a FM. A minority of results were disclosed by PCPs. Continued follow up is needed to determine long term outcomes. [Table: see text]
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