Uncovering therapeutically targetable mutations from The Cancer Genome Atlas (TCGA) whole-genome datasets

The systematic identification of therapeutically actionable genomic alterations across tumor types is essential to advance precision oncology. Using the CancerVision TM whole-genome analysis platform, we analyzed >8,000 whole-genome sequencing (WGS) samples spanning more than 30 cancer types to characterize clinically actionable mutations. Actionability was defined according to the Cancer Knowledgebase evidence levels, where Level A denotes biomarkers linked to FDA-approved on-label therapies. Overall, 2903 patients (~32%) harbored at least one Level A actionable alteration encompassing ~20,100 events (median 2 per sample). Level A on-label targets were detected in more than half of THCA (thyroid cancer), KIRC (kidney clear-cell), SKCM (skin cutaneous melanoma), BRCA (breast cancer), and COAD (colon adenocarcinoma), underscoring their clinical relevance. The ten most frequent Level A targets were PIK3CA, KRAS, BRAF, VHL, PTEN, ERBB2, BRCA1/2, NRAS, and EGFR , showing variable frequencies among cancer types. Among KRAS alterations, p.G12C was the predominant actionable hotspot, mainly in lung adenocarcinoma with a few cases in colorectal and rectal cancers. A total of 950 fusion targets were identified across the cohort. BRCA exhibited the highest frequency (45 cases; 2.5%), including 40 ESR1-CCDC170 fusions, followed by THCA (55 cases; 9.7%), dominated by CCDC6-RET (25 cases). NRG1 fusions were found in 145 samples (1.7%), markedly higher than the historical pan-cancer frequency (~0.2%). Other recurrent targetable fusions included NTRK (0.7%; 60 samples), RET (0.7%), ALK (0.7%), BRAF (0.6%), and FGFR (2.5%; 210 samples), the latter largely involving FGFR2 (~180 cases). Across all fusion classes, >80% retained the kinase domain, supporting oncogenic potential. Clinical-trial-matched targets were most commonly TP53, PIK3CA , and CDKN2A , reflecting their broad inclusion in precision-medicine studies. This comprehensive pan-cancer analysis defines the most extensive WGS-based landscape to date of actionable mutations and druggable fusions. The whole-genome approach enabled high-resolution detection of rare structural variants that are often missed by targeted sequencing panels, highlighting the potential of whole-genome profiling to uncover therapeutically relevant but under-recognized targets, supporting the integration of WGS into future tumor-agnostic clinical trial design.