Impact of XPO1 mutations on survival outcomes in metastatic non-small cell lung cancer (NSCLC)

Misako Nagasaka, Mohammad Fahad B. Asad, Mohammed Najeeb Al Hallak, Md Hafiz Uddin, Ammar Sukari, Yasmine Baca, Joanne Xiu, Dan Magee, Hirva Mamdani, Dipesh Uprety, Chul Kim, Bing Xia, Stephen V. Liu, Jorge J. Nieva, Gilberto Lopes, Gerold Bepler, Hossein Borghaei, Michael J. Demeure, Luis E. Raez, Patrick C. MaSonam Puri, W. Michael Korn, Asfar S. Azmi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)92-98
Number of pages7
JournalLung Cancer
Volume160
DOIs
StatePublished - Oct 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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