Cao Yingyue, Lan Dongmei, Ke Xianni, Zheng Wenyu, Zeng Jialong, Niu Niu, Fu Chunmei, Deng Wencui, Jin Shi
Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, China.
Department of Immunology, School of Basic Medicine and Forensic Medicine, North Sichuan Medical College, China.
Heliyon. 2024 May 31;10(11):e32287. doi: 10.1016/j.heliyon.2024.e32287. eCollection 2024 Jun 15.
is commonly mutated in lung adenocarcinoma (LUAD). However, its role in the pathogenesis of LUAD remains undefined. -mutant LUAD represents a distinct subset of non-small cell lung cancer (NSCLC). The function of in tumor pathogenesis is supposed to differ between -mutant and -wt LUAD. This study aimed to interrogate the prevalence of mutation in a large cohort of Chinese patients with LUAD and investigate the association of mutation with clinical and molecular characteristics of -mutant and -wt LUAD.
Tumor sequencing data from 2848 Chinese patients with LUAD were retrospectively reviewed and analyzed. The prevalence of was also compared with other three cohorts: OrigMed (n = 1222), MSKCC (n = 1267), and TCGA (n = 566). The associations of 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 mutation with clinical outcomes upon immunotherapy.
Our cohort showed a higher prevalence of in -mutant LUAD than in -wt LUAD (14.8 % vs. 6.5 %, p < 0.001). The enrichment of mutations in -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). mutations co-occurred more frequently with L858R mutations (23.7 %) than with other types of mutations (19 del: 7.7 %; other: 7.1 % in others, p < 0.001). In -mutant LUAD, 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 -mutant LUAD with concomitant mutation was not different from that those without mutations (41.8 % vs. 47.9 %, p = 0.566). In contrast, mutation occurred more frequently in -wt LUAD at stage II-IV (stage II: 12.0 %, stage III: 8.7 %, stage IV: 6.6 %) than at stage I (2.8 %). -wt LUAD with concomitant 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 -wt LUAD who also harbored loss of function (LOF) mutations had a longer median PFS upon immunotherapy than those with non-LOF mutations (7.15 m vs. 2.60 m, HR = 4.83 [1.30-17.94], p = 0.010).
We comprehensively investigated 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. mutation shows different associations with clinical and molecular characteristics between -mutant and -wt LUAD, suggesting a divergent mechanism between these two subsets via which 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.
在肺腺癌（LUAD）中常见突变。然而，其在LUAD发病机制中的作用仍不明确。 -突变型LUAD是非小细胞肺癌（NSCLC）的一个独特亚组。 在肿瘤发病机制中的功能在 -突变型和 -野生型LUAD之间可能有所不同。本研究旨在调查一大群中国LUAD患者中 突变的发生率，并研究 突变与 -突变型和 -野生型LUAD的临床及分子特征之间的关联。
回顾性分析2848例中国LUAD患者的肿瘤测序数据。 突变的发生率还与其他三个队列进行了比较：OrigMed（n = 1222）、MSKCC（n = 1267）和TCGA（n = 566）。评估了 突变与临床及分子特征的关联。使用182例接受PD-1抑制剂治疗的LUAD患者的外部队列来研究 突变与免疫治疗临床结局的关联。
我们的队列显示， -突变型LUAD中 突变的发生率高于 -野生型LUAD（14.8%对6.5%，p < 0.001）。在另一个中国队列（OrigMed：14.9%对7.8%，p < 0.001）中也观察到 -突变型LUAD中 突变的富集，但在两个西方队列中未观察到（MSKCC：7.4%对9.5%，p = 0.272；TCGA：8.1%对6.7%，p = 0.624）。 突变与L858R 突变同时发生的频率（23.7%）高于与其他类型的 突变（19号外显子缺失：7.7%；其他：其他类型为7.1%，p < 0.001）。在 -突变型LUAD中， 突变在I期（18.2%）和II期（21.8%）肿瘤中比在III期（9.4%）和IV期（11.3%）肿瘤中更常见（p < 0.001）。伴有 突变的 -突变型LUAD中PD-L1阳性表达的比例与无 突变的患者无差异（41.8%对47.9%，p = 0.566）。相比之下， 突变在II-IV期的 -野生型LUAD中（II期：12.0%，III期：8.7%，IV期：6.6%）比在I期（2.8%）更频繁发生。伴有 突变的 -野生型LUAD的PD-L1表达阳性比例（78.9%对61.9%，p = 0.014）和肿瘤突变负荷（8.97对2.99个突变/Mb，p < 0.001）高于无 突变的患者。伴有 功能丧失（LOF）突变的 -野生型LUAD患者在免疫治疗后的中位无进展生存期比有 非LOF突变的患者更长（7.15个月对2.60个月，HR = 翻页4.83 [1.30 - 17.94]，p = 0.010）。
我们全面调查了中国LUAD队列中的 突变。与西方队列相比，中国人群中EGFR突变型LUAD与EGFR野生型LUAD相比，RBM10突变显著富集。 突变在 -突变型和 -野生型LUAD之间与临床及分子特征表现出不同的关联，表明这两个亚组之间存在不同的机制，通过该机制 缺陷促成肿瘤发病机制。这些发现有助于我们了解LUAD的分子格局，并强调在癌症基因组学研究中考虑人群特异性因素的重要性。
