The discrepancy of somatic BRCA1/2 pathogenic variants from two different platforms in epithelial ovarian, fallopian tube, and peritoneal cancer

• Published in: Scientific reports Vol. 14; no. 1; pp. 25879 - 7
• Main Authors: Kim, Ji Hyun, Shin, Jun-Young, Park, Seog-Yun, Seo, Sang-Soo, Kang, Sokbom, Yoo, Chong Woo, Park, Sang-Yoon, Lim, Myong Cheol
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1517; 631/67/1517/1709; Adult; Aged; Biomarkers, Tumor - genetics; BRCA; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - pathology; Discordance; Fallopian tube; Fallopian Tube Neoplasms - genetics; Fallopian Tube Neoplasms - pathology; Female; Genetic analysis; Genetic profiling; Genetic screening; High-Throughput Nucleotide Sequencing - methods; Homologous recombination; HRD; Humanities and Social Sciences; Humans; Middle Aged; multidisciplinary; Mutation; Next-generation sequencing; Ovarian cancer; Ovarian Neoplasms - genetics; Peritoneal Neoplasms - genetics; Science; Science (multidisciplinary); Tumors; Genetic profiling; BRCA; HRD; Ovarian cancer
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-75230-6

The somatic BRCA1 or BRCA2 Pathogenic Variant (PV)/Likely PV (LPV) from Next Generation Sequencing (NGS) is the most important biomarker for PARP inhibitor use and maintenance-targeted therapies. A discrepancy in the detection rates of BRCA1 and BRCA2 PV/LPV was identified among the NGS platforms. The objective of this study was to compare the somatic BRCA results from two distinct platforms using the same cohort and to identify the causes of these differences. Patients with epithelial ovarian cancer who concurrently underwent tumor NGS using two different platforms between January 2022 and June 2023 were included in this study. The two platforms used were in-house tumor NGS (Illumina NextSeq 550Dx, SureSelectXT library kit, and datasets from 1000 Genomes, ESP6500, ExAC, and ClinVar) and GreenPlan homologous recombination deficiency (HRD) test (Illumina NextSeq 550Dx, customized Twist Bioscience library kit, and datasets from COSMIC and OncoKB). The results of somatic mutations in BRCA1 and BRCA2 were compared between the two platforms. Of the 118 patients, 11.9% ( n  = 14) exhibited a discordant interpretation of BRCA1 or BRCA2 between the two platforms. Eleven patients (9.3%) exhibited negative results in the in-house platform but positive results (eight seven as PV of BRCA1, one as PV of BRCA2, one as LPV of BRCA1, and two as LPV of BRCA2) in the GreenPlan HRD test, while three patients (2.6%) had positive BRCA pathogenic variants (two as PV of BRCA1 [c.3340G > T, c.5152 + 3 A > C], one as LPV of BRCA2 [c.8174G > T], and one as LPV of BRCA1 [c.5017_5019delCAC]) in the in-house platform but a negative result in the GreenPlan HRD test. The discordance rate of somatic BRCA1 or BRCA2 mutations from different platforms was approximately 12%. In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.