Misako Nagasaka1, Mohammad Fahad B Asad2, Mohammed Najeeb Al Hallak2, Md Hafiz Uddin2, Ammar Sukari2, Yasmine Baca3, Joanne Xiu3, Dan Magee3, Hirva Mamdani2, Dipesh Uprety2, Chul Kim4, Bing Xia5, Stephen V Liu4, Jorge J Nieva5, Gilberto Lopes6, Gerold Bepler2, Hossein Borghaei7, Michael J Demeure8, Luis E Raez9, Patrick C Ma10, Sonam Puri11, W Michael Korn3, Asfar S Azmi12. 1. Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA; Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. Electronic address: nagasakm@hs.uci.edu. 2. Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA. 3. Caris Life Sciences, Phoenix, AZ, USA. 4. Georgetown University, Washington, DC, USA. 5. USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 6. University of Miami Miller School of Medicine, Miami, FL, USA. 7. Fox Chase Cancer Center, Philadelphia, PA, USA. 8. Hoag Family Cancer Institute, Newport Beach, CA, USA; Translational Genomics Research Institute, Phoenix, AZ, USA. 9. Memorial Cancer Institute/Florida International University, Miami, FL, USA. 10. Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA. 11. Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA. 12. Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA. Electronic address: azmia@karmanos.org.
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.
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.
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