Pan-cancer characterization of RET structural variants reveals recurrent architectures and lineage-specific clinicogenomic patterns

Purpose RET structural variants (SVs) are clinically actionable oncogenic events with particular relevance in thyroid cancer, but their pan-cancer architecture, partner-gene diversity, and lineage-specific clinicogenomic context remain incompletely defined. Methods We performed a pan-cancer characterization of RET SVs across targeted sequencing, whole-exome sequencing, whole-genome sequencing, and RNA-derived datasets, including Memorial Sloan Kettering Cancer Center (MSKCC), The Cancer Genome Atlas (TCGA), Pan-Cancer Analysis of Whole Genomes (PCAWG), and an institutional lung cancer cohort. Results RET SVs were rare at the pan-cancer level but enriched in selected tumor types, particularly thyroid and lung carcinomas. Most recurrent events retained the 3′ kinase-encoding region of RET , most commonly exons 12–20. Partner-gene distribution was lineage-specific: KIF5B predominated in lung adenocarcinoma (LUAD), whereas CCDC6 and NCOA4 were enriched in thyroid carcinomas. In LUAD, lymph node metastases were significantly more frequent in KIF5B :: RET than CCDC6 :: RET cases. RET SV-positive colon adenocarcinomas were enriched for microsatellite instability phenotypes and pathogenic RNF43 mutations, whereas RET SV-positive LUADs showed enrichment for SETD2 mutations. In papillary thyroid carcinoma, RET SV-positive tumors were mutually exclusive with BRAF hotspot mutations, lower tumor mutational burden, higher RET mRNA expression, and an immune-inflamed phenotype characterized by increased lymphocyte infiltration, higher cancer-testis antigen scores, and enhanced T helper 1 (Th1)-associated immune activity. Conclusion These findings refine the molecular taxonomy of RET SVs and highlight thyroid carcinoma as a major lineage in which RET rearrangements define clinically relevant genomic and immune-contextual subgroups.