ArticleDiscover oncology2026
A mutational signature for brain metastasis tropism in lung adenocarcinoma.
Article in Discover oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundLung adenocarcinoma brain metastasis (LUAD-BM) is a leading cause of cancer-related mortality, yet the genomic determinants driving brain tropism and reliable predictive biomarkers remain poorly defined.
methodsWe analyzed the mutational profiling of 2602 primary LUAD and LUAD-BM samples. Differentially mutated genes were used to construct a mutational signature-based classification for BM tropism, which was further characterized by corresponding multi-omic data. Independent validation was conducted in TCGA (N = 503) and Oncosg (N = 302) cohorts.
resultsMutational profiling of 172 LUAD-BM revealed frequent alterations in TP53, EGFR, and KRAS, with enrichment of apoptosis-, E2F-, and cell cycle-related pathways. Twenty-five genes were identified as significantly more frequently mutated in LUAD-BM, most of which also displayed higher mutation allele frequencies and preferential enrichment in LUAD patients with isolated brain metastasis. Using this 25-gene mutational signature, primary LUAD samples were classified into three distinct clusters with significantly different survival outcomes. Cluster 3 was strongly associated with brain metastasis, accounting for 62% of LUAD-BM cases and 59% of LUAD patients with isolated brain metastasis, and showed the highest incidence of BM development (25.3%, P < 0.001). Meanwhile, Cluster 3 was characterized by markedly elevated TMB, extensive copy number variations across multiple chromosomes, and an almost universal TP53 mutation rate (99.9%), representing a highly unstable genomic subtype resembling LUAD-BM. The prognostic value of this classification was independently validated in TCGA-LUAD and Oncosg cohorts, where the mutation-defined clusters retained distinct survival patterns and genomic features. Transcriptomic analyses further demonstrated that Cluster 3 was enriched for cell cycle, mitotic, and chemokine signaling pathways, whereas Cluster 1 showed activation of lung function-associated pathways, highlighting the biological and clinical relevance of the mutation-based stratification.
conclusionWe identified a high-risk LUAD subtype defined by a distinct mutational and copy number landscape, providing a practical framework for brain metastasis risk stratification and potential guidance for targeted surveillance strategies.
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