Abstract 6460: Incidence of pathogenic germline variants and presumed germline pathogenic variants in Japanese lung cancer patients using comprehensive genomic profiling tests
Authors: Ueki Michiko , Watanabe Kousuke , Morishita Momoko , Fujii Koki , Ikushima Hiroki , Isago Hideaki , Oda Katsutoshi , Kage Hidenori 
Published: March 2024

Abstract
Introduction: Pathogenic germline variants (PGVs) and presumed germline pathogenic variants (PGPVs) are often detected with comprehensive genomic profiling (CGP) tests. Using the Center for Advanced Cancer Genomics and Therapeutics (C-CAT) database, we investigated the incidence of PGV and PGPV detected by CGP tests in Japanese lung cancer patients.
Methods: Among 3,240 lung cancer cases registered in C-CAT between June 2019 and August 2023, 321 were tumor/normal paired NCC Oncopanel (NOP), 773 were FoundationOne Liquid CDx (F1L), and 2,145 were tumor-only FoundationOne CDx (F1CDx). We analyzed cancer susceptibility genes in accordance with the national guideline. In F1L and F1CDx, PGPV was determined based on variant allele frequency (VAF) and medical history. Differences between groups in the detection of PGV and PGPV were tested using chi-squared test, and differences in age were tested using t-test.
Results: The incidence of PGV in NOP and PGPV in F1L and F1CDx were 4/321 (1.2%), 36/773 (4.7%), and 141/2145 (6.6%), respectively (NOP vs F1L vs F1CDx; p = 0.001 NOP vs F1L; p = 0.006, NOP vs F1CDx; p &lt; 0.001, F1L vs F1CDx;p=0.190). The 4 PGVs detected by NOP were in the ATM, BRCA2, MSH6, and TP53 genes. Notably, two out of four patients were in their 30s while the other two were in their 70s. In the F1L dataset, 36 patients (4.7%) had PGPV: 8 patients (1.0%) had PALB2, 6 patients (0.8%) had BRCA2, and 4 patients (0.5%) had CHEK2 variants. In the F1CDx dataset, 141 had PGPV: 19 patients (0.9%) each had BRCA1 or BRCA2 variants and 18 patients (0.8%) had PALB2 variant. There was no significant age difference between PGPV(-) and PGPV(+) patients (F1L:63.3 vs. 62.4 years; p = 0.938, F1CDx: 65.5 vs 65.0 years; p = 0.749). Most cases with PGV or PGPV were non-small cell lung cancer: 4/4 in NOP, 34/36 in F1L, and 110/141 in F1CDx.
Discussion: The incidence of PGV in lung cancer patients was at least 1% and found in both younger and older patients. A circulating tumor DNA panel and a tumor-only tissue panel detected PGPVs at a significantly higher rate than detection of true PGVs by tumor/normal paired tissue panel, suggesting the use of tumor/normal paired panels may mitigate the burden of both patients and clinicians with concerns from false positive PGPV. The majority of detected PGV/PGPV were in homologous recombination repair genes.
Citation Format: Michiko Ueki, Kousuke Watanabe, Momoko Morishita, Koki Fujii, Hiroki Ikushima, Hideaki Isago, Katsutoshi Oda, Hidenori Kage. Incidence of pathogenic germline variants and presumed germline pathogenic variants in Japanese lung cancer patients using comprehensive genomic profiling tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6460.