Open Access

NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer

  • Authors:
    • Herdee Gloriane C. Luna
    • Marcelo Severino Imasa
    • Necy Juat
    • Katherine V. Hernandez
    • Treah May Sayo
    • Gloria Cristal‑Luna
    • Sheena Marie Asur‑Galang
    • Mirasol Bellengan
    • Kent John Duga
    • Bien Brian Buenaobra
    • Marvin I. De Los Santos
    • Daniel Medina
    • Jamirah Samo
    • Venus Minerva Literal
    • Sullian Sy‑Naval
  • View Affiliations

  • Published online on: May 8, 2024     https://doi.org/10.3892/ol.2024.14436
  • Article Number: 303
  • Copyright: © Luna et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].

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Abstract

NK2 homeobox 1 (NKX2‑1) copy number alterations (CNAs) are frequently observed in lung cancer. However, little is known about the complete landscape of focal alterations in NKX2‑1 copy number (CN), their clinical significance and their therapeutic implications in non‑small cell lung cancer (NSCLC). The correlations between NKX2‑1 expression and EGFR driver mutations and programmed death ligand 1 (PD‑L1) co‑expression were studied using immunohistochemistry and PCR from the tumors of recruited Filipino patients (n=45). Clinical features of NSCLC with NKX2‑1 CNAs were resolved at the tumor and clonal levels using the molecular profiles of patients with lung adenocarcinoma and lung squamous cell carcinoma from The Cancer Genome Atlas (n=1,130), and deconvoluted single‑cell RNA‑seq data from the Bivona project (n=1,654), respectively. Despite a significant and positive correlation between expression and CN (r=0.264; P<0.001), NKX2‑1 CNAs exerted a stronger influence on the combined EGFR and PD‑L1 status of NSCLC tumors than expression. NKX2‑1 CN gain was prognostic of favorable survival (P=0.018) and a better response to targeted therapy. NKX2‑1 CN loss predicted a worse survival (P=0.041). Mutational architecture in the Y‑chromosome differentiated the two prognostic groups. There were 19,941 synonymous mutations and 1,408 genome‑wide CN perturbations associated with NKX2‑1 CNAs. Tumors with NKX2‑1 CN gain expressed lymphocyte markers more heterogeneously than those with CN loss. Higher expression of tumor‑infiltrating lymphocyte gene signatures in CN gain was prognostic of longer disease‑free survival (P=0.005). Tumors with NKX2‑1 CN gain had higher B‑cell (P<0.001) and total T‑cell estimates (P=0.003). NKX2‑1 CN loss was associated with immunologically colder tumors due to higher M2 macrophage infiltrates (P=0.011) and higher expression of immune checkpoint proteins, CD274 (P=0.025), VTCN1 (P<0.001) and LGALS9 (P=0.002). In conclusion, NKX2‑1 CNAs are associated with tumors that exhibit clinically diverse characteristics, and with unique oncogenic, immunological and prognostic signatures.
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July-2024
Volume 28 Issue 1

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Spandidos Publications style
Luna HC, Imasa MS, Juat N, Hernandez KV, Sayo TM, Cristal‑Luna G, Asur‑Galang SM, Bellengan M, Duga KJ, Buenaobra BB, Buenaobra BB, et al: NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer. Oncol Lett 28: 303, 2024.
APA
Luna, H.C., Imasa, M.S., Juat, N., Hernandez, K.V., Sayo, T.M., Cristal‑Luna, G. ... Sy‑Naval, S. (2024). NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer. Oncology Letters, 28, 303. https://doi.org/10.3892/ol.2024.14436
MLA
Luna, H. C., Imasa, M. S., Juat, N., Hernandez, K. V., Sayo, T. M., Cristal‑Luna, G., Asur‑Galang, S. M., Bellengan, M., Duga, K. J., Buenaobra, B. B., De Los Santos, M. I., Medina, D., Samo, J., Literal, V. M., Sy‑Naval, S."NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer". Oncology Letters 28.1 (2024): 303.
Chicago
Luna, H. C., Imasa, M. S., Juat, N., Hernandez, K. V., Sayo, T. M., Cristal‑Luna, G., Asur‑Galang, S. M., Bellengan, M., Duga, K. J., Buenaobra, B. B., De Los Santos, M. I., Medina, D., Samo, J., Literal, V. M., Sy‑Naval, S."NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer". Oncology Letters 28, no. 1 (2024): 303. https://doi.org/10.3892/ol.2024.14436