■RBM10通常在肺腺癌(LUAD)中突变。然而,其在LUAD发病机制中的作用尚不明确。EGFR突变型LUAD代表了非小细胞肺癌(NSCLC)的一个独特子集。RBM10在肿瘤发病机制中的功能在EGFR突变体和EGFR-wtLUAD之间可能有所不同。本研究旨在调查大量中国LUAD患者中RBM10突变的患病率,并研究RBM10突变与EGFR突变体和EGFR-wtLUAD的临床和分子特征的关系。
■对2848例中国LUAD患者的肿瘤测序数据进行回顾性分析。RBM10的患病率也与其他三个队列进行了比较:OrigMed(n=1222),MSKCC(n=1267),和TCGA(n=566)。评估RBM10突变与临床和分子特征的关联。使用182名接受PD-1抑制剂的LUAD患者的外部队列研究RBM10突变与免疫治疗后临床结果的关联。
■我们的队列显示,RBM10在EGFR突变型LUAD中的患病率高于EGFR-wtLUAD(14.8%vs.6.5%,p<0.001)。在另一个中国队列中也发现了EGFR突变LUAD中RBM10突变的富集(OrigMed:14.9%vs.7.8%,p<0.001),但不是在两个西方队列中(MSKCC:7.4%vs.9.5%,p=0.272;TCGA:8.1%vs.6.7%,p=0.624)。与其他类型的EGFR突变相比,RBM10突变与EGFRL858R突变(23.7%)共同发生的频率更高(19del:7.7%;其他:其他:7.1%,p<0.001)。在EGFR突变型LUAD中,RBM10突变更常见于I期(18.2%)和II期(21.8%)。III期(9.4%)和IV期(11.3%)肿瘤(p<0.001)。伴随RBM10突变的EGFR突变型LUAD中PD-L1阳性表达的比例与没有RBM10突变的比例没有差异(41.8%vs.47.9%,p=0.566)。相比之下,RBM10突变在II-IV期EGFR-wtLUAD中发生频率更高(II期:12.0%,第三阶段:8.7%,第四阶段:6.6%)比第一阶段(2.8%)。伴随RBM10突变的EGFR-wtLUAD的PD-L1表达阳性率较高(78.9%vs.61.9%,p=0.014)和更高的肿瘤突变负荷(8.97vs.2.99muts/Mb,p<0.001)比没有的。与具有RBM10非LOF突变的患者相比,也具有RBM10功能丧失(LOF)突变的EGFR-wtLUAD患者在免疫治疗后的中位PFS更长(7.15mvs.2.60米,HR=4.83[1.30-17.94],p=0.010)。
■我们全面调查了中国LUAD队列中的RBM10突变。与西方队列相比,在中国人群中,与EGFR野生型LUAD相比,EGFR突变型LUAD中RBM10突变显著富集.RBM10突变与EGFR突变体和EGFR-wtLUAD之间的临床和分子特征显示出不同的关联,提示这两个亚群之间存在不同的机制,RBM10缺乏通过这些机制促进肿瘤的发病机制。这些发现有助于我们对LUAD分子景观的理解,并强调了在癌症基因组学研究中考虑人群特异性因素的重要性。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.