Clinico-genomic landscape and prognostic impact of APC/CTNNB1 oncogenic alterations in non–small cell lung cancer.

作者：Leonardo Brunetti, Valentina Santo, Eleonora Gariazzo, Cassio Murilo Hidalgo-Filho, Federica Pecci, Xinan Wang, Narjust Florez, Jaclyn LoPiccolo, Hugo Aerts, Biagio Ricciuti · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.8552 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics、Wnt/β-catenin signaling in development and cancer

8552 Background: Genomic activation of the WNT/β-catenin pathway via APC loss-of-function or activating CTNNB1 mutations is well established across multiple cancer types, but its prevalence and genomic context in non–small cell lung cancer (NSCLC) remain poorly characterized. We systematically characterized the prevalence of APC and CTNNB1 alterations in NSCLC, and defined their mutational landscape and prognostic impact. Methods: We conducted a multicenter cohort study including patients with NSCLC whose tumors underwent targeted exon sequencing at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Tumors were classified as APC-mutated, CTNNB1-mutated, or WNT-mutated (APC and/or CTNNB1 mutated). Pathogenic alterations were defined as oncogenic or likely oncogenic per OncoKB, or as missense variants with a REVEL score > 0.5. Gene enrichment analyses used gene-wise logistic regression adjusted for tumor mutational burden (TMB), testing genes meeting a predefined prevalence threshold, with Bonferroni correction within each analysis. Results: In the DFCI cohort (N = 4,717), APC or CTNNB1 alterations were identified in 4.5% of NSCLC (212/4,717), including APC in 1.7% (79/4,717) and CTNNB1 in 2.8% (133/4,717), and were mutually exclusive. APC alterations were predominantly loss-of-function events (85.3% of qualifying APC variants) and splice-region/site variants (14.8%). CTNNB1 alterations were all missense mutations (100%), clustering in ex...