Abstract 2125: Evaluating pathogenic germline variants in checkpoint kinase 2 (CHEK2) in ovarian germ cell tumors

Introduction: Ovarian germ cell tumors (OGCT) are exceedingly rare cancers primarily afflicting young girls leading to potentially disproportionate life years lost. In the United States, the 30-year age-adjusted incidence rate per 100,000 women-years is 0.338. Due in part to the infrequency of this neoplasm, to date no Mendelian OGCT predisposition gene has been identified, thus limiting the ability to provide molecular-based personalized clinical care. Recently, we showed that germline complete and partial loss-of-function variants in CHEK2 confer an increased susceptibility to testicular germ cell tumors, a cancer with similar pathological and cytogenetic features. In this study, we hypothesized that inherited CHEK2 defects may account for a proportion of OGCT heritability and provide clinically informative markers for OGCT susceptibility. Methods: Using a deep-learning-based germline variant calling algorithm and identical quality control standards, a targeted case-control gene-based enrichment analysis of pathogenic germline CHEK2 variants was performed in 49 OGCT patients and 1,873 ancestry-matched cancer-free adults. A secondary gene-level enrichment analysis of 50 established cancer predisposition DNA repair and cell cycle genes (DRG) was conducted in the same cohort. Results: In our cases (n=49), the coding bases of CHEK2 were sufficiently covered by over 15 reads 99.97% of the time. For our controls (n=1,873), the coding bases of CHEK2 was sufficiently covered by over 15 reads 96.05% of the time. There was no significant difference in the coverage of CHEK2 between cases and controls (P=0.96). We detected two OGCT patients with a rare, likely pathogenic CHEK2 variant. These two variants predicted transcript consequence were missense (c.1412C>T) and frameshift (c.1229del). Our analysis found CHEK2 pathogenic variants as significantly enriched in OGCT cases compared to controls. Specifically, we identified that OGCT patients were seven times as likely to carry a rare, pathogenic germline mutation in CHEK2 compared to controls (n=2, 4.08%, OR=7.18, 95% CI=1.11- 30.94, P=0.04). The CHEK2 low-penetrance allele, c.599T>C, was not observed in our case cohort. With respect to pathogenic alterations found in DRG, 20.41% (95% CI= 3.05-14.59) of our cases had a rare likely pathogenic mutation in a DRG compared to 6.03% (95% CI= 3.05-14.59) of our controls. Aside from CHEK2, there was no DRG significantly enriched for pathogenic variants in our cases. Conclusion: Our case-control analysis provides preliminary evidence for CHEK2 as a novel moderately-penetrant OGCT risk gene that may explain a portion of the monogenic heritability of OGCT. Critically, these findings require validation using other cohorts. CHEK2 is a known risk gene in breast cancer and colorectal cancer. Citation Format: Sabrina Yvonne Camp, Seunghun Han, Saud H. AlDubayan, Eliezer M. Van Allen. Evaluating pathogenic germline variants in checkpoint kinase 2 (CHEK2) in ovarian germ cell tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2125.