The online version of this article (https://doi.org/10.1186/s12890-017-0542-z) contains supplementary material, which is available to authorized users.
Jorge Moisés and Alfons Navarro equally contributed to this paper.
Mariano Monzó and Ramón María Marrades equally contributed as senior authors.
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.
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.
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).
NKX2–1 expression impacts prognosis in early-stage NSCLC patients, particularly in those with neither TP53 nor KRAS mutations.
Additional file 1: Figure S1. NKX2–1 expression according to TTF-1 immunohistochemistry. Figure S2. Kaplan Meier analysis of disease-free survival according to NKX2–1 expression levels in (A) the entire cohort and (B) patients with stage I disease. Figure S3. Kaplan Meier analysis of overall survival according to miR-365 expression levels in (A) the entire cohort and (B) patients harboring neither TP53 nor KRAS mutations. Figure S4. Kaplan Meier analysis of overall survival according to NKX2–1 expression levels in (A) patients with wild-type TP53, (B) patients with TP53 mutations, (C) patients with wild-type KRAS, and (D) patients with KRAS mutations. Figure S5. Kaplan Meier analysis of the impact of NKX2–1 in overall survival in stage I disease (A) WT TP53 patients, (B) TP53 mutated patients, (C) KRAS WT patients, and (D) KRAS mutated patients. (PDF 276 kb)12890_2017_542_MOESM1_ESM.pdf
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- NKX2–1 expression as a prognostic marker in early-stage non-small-cell lung cancer
Joan Josep Castellano
Ramón María Marrades
- BioMed Central
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