Pathogenic Germline Variants in BRCA1/2 and p53 Identified by Real-world Comprehensive Cancer Genome Profiling Tests in Asian Patients

Abstract

Abstract Cancer genome profiling (CGP) occasionally identifies pathogenic germline variants (PGV) in cancer susceptibility genes (CSG) as secondary findings. Here, we analyzed the prevalence and clinical characteristics of PGVs based on nationwide real-world data from CGP tests in Japan. We analyzed the genomic information and clinical characteristics of 23,928 patients with solid cancers who underwent either tumor-only (n = 20,189) or paired tumor-normal (n = 3,739) sequencing CGP tests between June 2019 and December 2021 using the comprehensive national database. We assigned clinical significance for all variants and highlighted the prevalence and characteristics of PGVs. Our primary analysis of the tumor-normal sequencing cohort revealed that 152 patients (4.1%) harbored PGVs in 15 CSGs. Among 783 germline variants, 113 were annotated as PGVs, 70 as benign variants, and 600 as variants of uncertain significance. The number of PGVs identified was highest in BRCA1/2, with 56, followed by TP53, with 18. PGVs were the most prevalent in ovarian and peritoneal cancers, including among cancer types common in Asia. In the tumor-only sequencing cohort, of the 5,184 pathogenic somatic variants across 26 CSGs, 784 (15.1%) were extracted according to the European Society for Medical Oncology recommendations for germline-focused tumor analysis. The prevalence of PGVs was similar to that previously reported in Europe and the United States. This is the largest analysis based on real-world tumor-normal sequencing tests in Asia. The more widespread use of the tumor-normal sequencing CGP test could be reasonable for evaluating PGVs. Significance: We analyzed real-world data from over 23,000 patients in Japan, revealing 4.1% harbored PGVs, particularly in BRCA1/2 and TP53, in CSGs. It highlights the prevalence of PGVs in Asian populations and supports the broader adoption of tumor-normal sequencing CGP tests for PGV evaluation.