Abstract 3324: Co-occurrence of gene fusions with SNV/Indels and with CNVs on solid tumors in a cohort of 795 patients from the community setting
Authors: Chaugiang Duong, Nathan Montgomery, Derek Lyle, Fernando Lopez-Diaz
Journal: Cancer Research (2025)

Abstract Background: Co-occurrence of gene alterations often plays a relevant role in the selection of potential targeted therapies for a cancer patient. It has been reported that patients with fusions respond to fusion-targeted therapy regardless of the tissue type. Less is known about the co-occurrence of SNVs and Indels with gene fusions and copy number variation. Methods: Data from 795 patients tested with a CGP assay that interrogated SNVs/Indels on 517 genes, fusions of 59 genes, and CNV on 55 genes were included in the study. Variant clinical significance was determined as described by the FDA-recognized OncoKB database or the National Comprehensive Cancer Network, NCCN. The study was performed with an IRB approved research protocol. Results: We examined the co-occurrence of copy number variation, RNAseq fusion detection, and actionable SNV and Indel mutations in community care settings to understand their combined potential clinical implications. We analyzed the co-occurrence of fusion events with targetable mutations, the overlap of fusions with copy number variation detection, and simultaneous copy number variation and actionable SNV/Indels. Roughly 5.3% (38/ 713) of tumors with pathogenic/likely pathogenic OncoKB gene mutation also had a fusion event. Conversely, 80.9% (38/47) of patients harboring a gene fusion had pathogenic OncoKB mutation(s). When analyzed alone, amongst the 40 fusions, the most frequent were SDCCAG8::AKT3 (n=5), TMPRSS2::ERG (n=4), ESR1::CCDC170, and ROS1 fusions (n=3). Fifteen (15) of these fusions have a potentially actionable fusion as defined by NCCN and/or OncoKB database. ROS1 fusions most commonly had TP53 mutations (66.66%), with equal detection of other pathogenic oncoKB co-mutations in BRCA2, EGFR, and BRAF. Meanwhile, 6 of the patients had PIK3CA oncogenic mutations with an available therapeutic selection, and 2 had a fusion that offers additional clinical implications. Additionally, ESR1 was the most frequent fusion partner with PIK3CA co-mutation with OncoKB described actionability. The most common SNV/Indel mutation observed was TP53, with 31 unique tumors bearing co-occurring TP53 mutation with a fusion. In addition, 36.2% (17/47) of fusion positive tumors had concurrent copy number variation, whereas 6.9% (17/245) of tumors with copy number alteration detection (n=245) concurrently had a fusion. Moreover, 32.0% (228/713) of samples with pathogenic gene mutation also had copy number variation(s). Conversely, 93.1% (228/245) of tumors with copy number variation had pathogenic OncoKB mutation. Conclusion: Genomic rearrangements, albeit relatively infrequent, can often be concomitantly expressed in the context of other actionable DNA mutations or CNVs, which can lead to better understanding of tumorigenesis and improve clinical care as tumors are tested with comprehensive genomic profiling assays. Citation Format: Chaugiang Duong, Nathan Montgomery, Derek Lyle, Fernando Lopez-Diaz. Co-occurrence of gene fusions with SNV/Indels and with CNVs on solid tumors in a cohort of 795 patients from the community setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3324.