Background

Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes.

Methods

Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate.

Results

Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144- 3.264 p = 0.012). XPO1 amplification was not associated with survival.

Conclusions

XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

中文翻译：

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XPO1突变对转移性非小细胞肺癌（NSCLC）生存结果的影响

背景

核蛋白转运对于指导重要蛋白质和 RNA 在细胞核和细胞质之间的运输至关重要。细胞核中蛋白质的输出主要受输出蛋白 1 (XPO1) 的调节。在癌症中，XPO1 几乎普遍过度活跃，可以促进重要的肿瘤抑制因子向细胞质输出。目前，没有研究评估 XPO1 在 NSCLC 中的扩增和突变以及对结果的影响。

方法

使用下一代测序 (NGS) (NextSeq, 592 Genes)、免疫组织化学 (IHC) 和全转录组测序 (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ) 分析肿瘤样本。从保险索赔数据中提取生存率，并使用 Kaplan-Meier 估计从组织收集到最后一次接触的时间计算。

结果

在测序的 18,218 个 NSCLC 肿瘤中，26 个具有 XPO1 突变，24 个具有扩增。XPO1 突变肿瘤更可能具有高 TMB（79% 对 52%，p  =  0.007）并且不太可能具有高 PD-L1（32% 对 68%，p  =  0.03）。KRAS 共突变见于 19% (n  =  5)，EGFR 共突变很少见 (n  =  2)。在有临床数据的17449个NSCLC肿瘤中，有24个XPO1突变体。XPO1 突变体和 WT 之间的存活比较显示与 1.932 的风险比 (HR) 呈负相关 (95% CI: 1.144-3.264 p  =  0.012)。XPO1 扩增与生存无关。

结论

XPO1 致病性突变与非小细胞肺癌患者的不良生存率相关。尽管 XPO1 突变在 NSCLC 中很少见，但仍需要进一步研究以评估其与治疗反应的关联。