Risk of ovarian cancer in women with a pathogenic or likely pathogenic variant in NBN: a systematic review and meta-analysis
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Authors
Ganesan, Subhasheenee
Mansour, Lea
Dibden, Amanda
Sideris, Michail
Malan, Antonetta
Oxley, Samuel
Kalra, Ashwin
Sia, Jacqueline
Wei, Xia
Deshmukh, Priyanka
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2026
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OBJECTIVE: NBN is a putative ovarian cancer susceptibility gene. The association between a pathogenic variant in NBN and ovarian cancer is not well established. We aimed to estimate the ovarian cancer risk in unselected women with an NBN pathogenic variant. DATA SOURCES: PubMed and Embase searched from inception to January 2026. ELIGIBILITY CRITERIA: Population: Women diagnosed with ovarian cancer undergoing germline sequencing of NBN (intervention). STUDY APPRAISAL AND SYNTHESIS METHODS: We followed a prospective protocol as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42024567791). The number of NBN pathogenic variants in ovarian cancer cases in included studies was pooled and an estimated odds calculated. This was compared to the odds of an NBN loss-of-function variant in Genome Aggregation Database v4.1 controls of matched ethnicities to obtain the odds ratio of ovarian cancer with an NBN pathogenic variant. We performed prespecified subgroup analyses for high-grade serous carcinoma and non-high-grade serous carcinoma, and those with a family history of ovarian cancer. RESULTS: Searches yielded 9025 studies; 57 studies (n=40, 537) were included in our initial analysis: 36 in majority White cohorts (n=33, 822) and 21 in non-White cohorts (n=6715). In the White cohorts, the odds ratio of ovarian cancer with an NBN pathogenic variant was 1.68 (95% confidence interval, 1.37-2.07; P<.001), and the derived relative risk and lifetime risk of ovarian cancer 1.66% and 3.32%, respectively. For the most common pathogenic variant c.657_661del, the odds ratio was 2.69 (95% confidence interval, 1.58-4.57; P<.001), and the relative risk and lifetime risk of ovarian cancer 2.60% and 5.2%, respectively. The odds ratio of high-grade serous carcinoma and non-high-grade serous carcinoma is 1.58 (95% confidence interval, 1.02-2.45; P=.039) and 2.43 (95% confidence interval, 1.56-3.81; P<.001), respectively. Data in non-White cohorts and in ovarian cancer cases with family history were insufficient for any meaningful inference. CONCLUSION: There is a clear association between an NBN pathogenic variant and ovarian cancer in the White population, and this may be stronger with non-high-grade serous carcinoma compared to high-grade serous carcinoma. Further data are required to confirm the association with family history or establish any association in the non-White population. NBN pathogenic variants could be combined with other nongenetic and genetic (polygenic risk score) ovarian cancer risk factors using complex ovarian cancer risk-prediction models going forward, to identify several NBN-positive women at an ovarian cancer risk level for offering surgical prevention.
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American Journal of Obstetrics and Gynecology