Frequent RBM10 Comutation and a Mutually Exclusive Relationship With Other TP53 Pathway Aberrations in Early-Stage Non-Small-Cell Lung Cancer with EGFR Mutation.

RNA-binding motif 10 (RBM10) mutation in non-small-cell lung cancer (NSCLC) is associated with decreased sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in vitro and in patients who received osimertinib as neoadjuvant treatment or palliative systemic therapy. The incidence of this mutation in early-stage NSCLC and the relationship with other mutations are unknown. We analyzed the clinical and genomic data of 190 patients with NSCLC who underwent surgical resection between June 2022 and April 2024. Genomic data were obtained from whole-exome sequencing performed in an ongoing multicenter prospective observational study. RBM10 mutation was detected in 17 of 152 patients with nonsquamous NSCLC (11%) and not detected in 38 patients with squamous cell carcinomas. The incidences of RBM10 mutation were higher in tumors with EGFR mutation (21%) and tumors with KRAS mutation (12%) compared with those without EGFR/KRAS mutations (2%, P < .001 and P = .07, respectively). In tumors with EGFR mutation (N = 68), RBM10 mutation was significantly associated with age (> 76 years, P < .01), the presence of ground-glass opacity (P < 0.05), and histological grade 1 (P < .05). We observed mutually exclusive relationships between RBM10 mutation, TP53 mutation, and MDM2 gene amplification, and a high incidence of RBM10 mutation or MDM2 gene amplification in tumors with EGFR L858R mutation/uncommon mutation. RBM10 mutation is frequent in Japanese patients with NSCLC with EGFR mutation, especially those with L858R or uncommon mutations, and was associated with late-onset and features of indolent tumor growth.