Detection of germline large genomic rearrangements in BRCA1/2 genes by a capture-based NGS panel reveals its contribution to Chinese patients with solid tumors

Background: Germline mutations in BRCA1/2 genes have been found associate with risk to develop breast and ovarian cancer in women. Patients with these mutations are also highly sensitive to PARP inhibitors. However, current NGS-based method lacks the capability to accurately detect large genomic rearrangements (LGR) including exon level deletions and duplications. Method: We have enhanced our capture-based NGS panel and developed an algorithm to detect LGRs in BRCA1/2 genes. We applied the method to retrospectively profile germline DNA from over 14,000 patients with solid tumors, including 367 ovarian cancers and 574 breast cancers. Samples with positive test results for exon level deletions or duplications were subsequently confirmed by MLPA. Results: Out of the 14,000 patients, we identified 19 patients with exon level deletions (BRCA1, n = 16; BRCA2, n = 3) and 7 with duplications (BRCA1, n = 6; BRCA2, n = 1). The germline LGR events were predominantly found in ovarian and breast cancer patients with a frequency of 1.9% (7/367) in ovarian cancer and a frequency of 1.2% (7/574) in breast cancer. We also observed occasional findings in non-small cell lung cancer, colorectal cancer as well as gastric cancer. From these LGRs, BRCA1 exon 2del (n = 4), BRCA1 exon 7del (n = 4) and BRCA1 exon 17-18del (n = 3) are the most recurrent LGRs observed. Conclusion: We here report a method to comprehensively evaluate the germline LGRs in BRCA1 and BRCA2 genes using the capture-based NGS panel. We verified the results by MLPA as an orthogonal assay and report the population frequency of LGRs occurrence in Chinese patients with solid tumors. Citation Format: Jing Li, Bo Yang, Kefei Huang, Changhao Liu, Hua Dong, Jie Wang, Fugen Li, Zhong-qiu Lin. Detection of germline large genomic rearrangements in BRCA1/2 genes by a capture-based NGS panel reveals its contribution to Chinese patients with solid 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 4289.