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

[BACKGROUND] 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.

[MATERIALS AND METHODS] 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.

[RESULTS] 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.

[CONCLUSION] 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.