Germline pathogenic variants detected by GenMineTOP: insight from a nationwide tumor/normal paired comprehensive genomic profiling test, in Japan.

Abstract

Comprehensive genomic profiling (CGP) expands treatment options for solid tumor patients and identifies hereditary cancers. However, in Japan, confirmatory tests have been conducted in only 31.6% of patients with presumed germline pathogenic variants (GPVs) detected through tumor-only testing. Paired tumor-normal analysis enables differentiation between somatic and germline variants. GenMineTOP, covered by Japan's national health insurance since August 2023, analyzes paired samples and reports GPVs in 40 genes. This study provides an initial characterization of GPVs based on clinical findings collected during the first year of GenMineTOP implementation. We analyzed 1356 solid tumor patients who underwent GenMineTOP testing in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between August 2023 and July 2024, focusing on GPV detection rates, gene distribution, and comparisons with other CGP tests. Among the analyzed cancer types, GenMineTOP had a higher proportion of CNS/brain, soft tissue, bone, and head and neck cancers compared to other CGP tests. GPVs were detected in 73 patients (5.4%), with 38.2% classified as off-tumor. HR-related GPVs (ATM, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D) were found in both males (median age: 69) and females (median age: 54). Among males, 57.9% were aged 65 or older. GPVs may be detected in any cancer patients, including those with off-tumor findings, particularly in older male patients, especially in HR-related genes. These findings support the use of paired CGP to improve the diagnosis of hereditary cancers that could otherwise remain undetected.