ABSTRACT
Background:
RBM10 is commonly mutated in
lung adenocarcinoma (LUAD). However, its
role in the pathogenesis of LUAD remains undefined. EGFR-mutant LUAD represents a distinct subset of
non-small cell lung cancer (NSCLC). The function of RBM10 in
tumor pathogenesis is supposed to differ between EGFR-mutant and EGFR-wt LUAD. This study aimed to interrogate the
prevalence of RBM10
mutation in a large cohort of
Chinese patients with LUAD and investigate the
association of RBM10
mutation with clinical and molecular characteristics of EGFR-mutant and EGFR-wt LUAD.
Methods:
Tumor sequencing data from 2848
Chinese patients with LUAD were retrospectively reviewed and analyzed. The
prevalence of RBM10 was also compared with other three cohorts OrigMed (n = 1222), MSKCC (n = 1267), and TCGA (n = 566). The
associations of RBM10
mutation with clinical and molecular characteristics were assessed. An external cohort of 182
patients with LUAD
who received PD-1 inhibitor were used to investigate the
association of RBM10
mutation with clinical outcomes upon
immunotherapy.
Results:
Our cohort showed a higher
prevalence of RBM10 in EGFR-mutant LUAD than in EGFR-wt LUAD (14.8 % vs. 6.5 %, p < 0.001). The enrichment of RBM10
mutations in EGFR-mutant LUAD was also seen in another
Chinese cohort (OrigMed 14.9 % vs. 7.8 %, p < 0.001), but not in the two western cohorts (MSKCC 7.4 % vs. 9.5 %, p = 0.272; TCGA 8.1 % vs. 6.7 %, p = 0.624). RBM10
mutations co-occurred more frequently with EGFR L858R
mutations (23.7 %) than with other types of EGFR
mutations (19 del 7.7 %; other 7.1 % in others, p < 0.001). In EGFR-mutant LUAD, RBM10
mutations were more commonly found in stage I (18.2 %) and II (21.8 %) vs. stage III (9.4 %) and IV (11.3 %)
tumors (p < 0.001). The proportion of PD-L1 positive expression in EGFR-mutant LUAD with concomitant RBM10
mutation was not different from that those without RBM10
mutations (41.8 % vs. 47.9 %, p = 0.566). In contrast, RBM10
mutation occurred more frequently in EGFR-wt LUAD at stage II-IV (stage II 12.0 %, stage III 8.7 %, stage IV 6.6 %) than at stage I (2.8 %). EGFR-wt LUAD with concomitant RBM10
mutations had higher proportions of PD-L1 expression positivity (78.9 % vs. 61.9 %, p = 0.014) and higher
tumor mutational load (8.97 vs. 2.99 muts/Mb, p < 0.001) than those without.
Patients with EGFR-wt LUAD
who also harbored RBM10 loss of function (LOF)
mutations had a longer median PFS upon
immunotherapy than those with RBM10 non-LOF
mutations (7.15 m vs. 2.60 m, HR = 4.83 [1.30-17.94], p = 0.010).
Conclusion:
We comprehensively investigated RBM10
mutations in a
Chinese cohort with LUAD. Compared to western cohorts, a significant enrichment of RBM10
mutations in EGFR-mutant LUAD compared to EGFR-wildtype LUAD in the
Chinese population. RBM10
mutation shows different
associations with clinical and molecular characteristics between EGFR-mutant and EGFR-wt LUAD, suggesting a divergent mechanism between these two subsets via which RBM10
deficiency contribute to
tumor pathogenesis. The findings contribute to our
understanding of the molecular landscape of LUAD and highlight the importance of considering
population-specific factors in
cancer genomics research.