NKX2–1 expression as a prognostic marker in early-stage non-small-cell lung cancer

• Main Authors: Jorge Moisés, Alfons Navarro, Sandra Santasusagna, Nuria Viñolas, Laureano Molins, José Ramirez, Jeisson Osorio, Adela Saco, Joan Josep Castellano, Carmen Muñoz, Sara Morales, Mariano Monzó, Ramón María Marrades
• Format: Article
• Language: English
• Published: BMC 2017-12-01
• Series: BMC Pulmonary Medicine
• Subjects: NKX2–1; microRNA; TP53; NSCLC; miR-365; miR-33a
• Online Access: http://link.springer.com/article/10.1186/s12890-017-0542-z

Abstract Background NKX2–1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2–1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2–1: miR-365, which targets NKX2–1; and miR-33a, which is downstream of NKX2–1. We have examined the effect of NKX2–1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR. Methods mRNA and miRNA expression was determined using TaqMan assays in 110 early-stage NSCLC patients. TP53, KRAS, and EGFR mutations were assessed by Sanger sequencing. Results NKX2–1 expression was upregulated in never-smokers (P = 0.017), ADK (P < 0.0001) and patients with wild-type TP53 (P = 0.001). A negative correlation between NKX2–1 and miR-365 expression was found (ρ = −0.287; P = 0.003) but there was no correlation between NKX2–1 and miR-33a expression. Overall survival (OS) was longer in patients with high expression of NKX2–1 than in those with low expression (80.8 vs 61.2 months (P = 0.035), while a trend towards longer OS was observed in patients with low miR-365 levels (P = 0.07). The impact of NKX2–1 on OS and DFS was higher in patients with neither TP53 nor KRAS mutations. Higher expression of NKX2–1 was related to higher OS (77.6 vs 54 months; P = 0.017) and DFS (74.6 vs 57.7 months; P = 0.006) compared to low expression. The association between NKX2–1 and OS and DFS was strengthened when the analysis was limited to patients with stage I disease (P = 0.005 and P=0.003 respectively). Conclusions NKX2–1 expression impacts prognosis in early-stage NSCLC patients, particularly in those with neither TP53 nor KRAS mutations.