Comprehensive genomic landscape of ERBB2 in Chinese GI tumors: mutation-centered landscapes and precision treatment opportunities

Background: ERBB2 aberrations are established oncogenic drivers with validated therapeutic relevance in breast cancer and emerging indications across solid tumors. In gastrointestinal malignancies, the prevalence, molecular contexts, and therapeutic implications of ERBB2 alterations remain incompletely defined, particularly for mutation-driven (non-amplified) disease. Objectives: This study aimed to delineate the genomic landscape of ERBB2 alterations across colorectal cancer (CRC) and gastric cancer (GC), with emphasis on mutation versus amplification subtypes and their associated molecular contexts. Design: This was a retrospective observational genomic cohort study based on next-generation sequencing (NGS) data from patients with gastrointestinal malignancies. Methods: Tumors harboring ERBB2 alterations were identified through targeted NGS. Variants were annotated using InterVar and classified according to oncogenic significance. Alterations were mapped to HER2 functional domains and integrated with co-mutation patterns, copy number profiles, tumor mutational burden (TMB), and microsatellite instability (MSI) status to characterize subtype-specific genomic features. Results: Across CRC and GC, ERBB2 mutations predominantly clustered within the HER2 kinase domain, with recurrent hotspots (R678Q, S310F/Y, L755S, V842I) largely classified as oncogenic or likely oncogenic. In CRC, ERBB2-mutant tumors frequently co-harbored alterations in APC, TP53, PIK3CA, ARID1A, and SMAD4, whereas ERBB2-amplified tumors showed co-gains in RARA, TOP2A, and SMARCE1. In GC, mutation-positive cases were enriched for APC, TP53, ARID1A, MUC16, and LRP1B alterations, while amplification was associated with EGFR and cell cycle regulators. Oncogenic ERBB2 mutation subgroups exhibited higher TMB and MSI-H enrichment than amplification-positive counterparts, with no material differences in overall copy-number burden between subtypes. These patterns indicate that non-amplified ERBB2-mutant tumors form a genomically distinct subset with potential immunogenic features. Conclusion: ERBB2 alterations in CRC and GC converge on recurrent kinase domain hotspots but arise within tumor type-specific genomic milieus that likely influence therapeutic response. Compared with amplification, oncogenic ERBB2 mutations are preferentially associated with higher TMB/MSI-H and characteristic co-mutation signatures, supporting the clinical evaluation of mutation-selective HER2 inhibitors and rational combinations with immune checkpoint blockade. Our findings expand the molecular epidemiology of ERBB2 in Chinese GI cohorts, suggesting potential implications for resistance to standard chemotherapy or anti-EGFR strategies in select settings.