HOX genes, grouped in four clusters in humans (HOXA-D), encode for transcription factors that are master regulators of embryonic development and oncogenesis. HOXA cluster, located in chromosome 7, play a critical role in the patterning of tissues with mesodermal components such as lungs. Long non-coding RNAs (lncRNAs) are especially abundant in the HOXA cluster (HOXA10-AS, HOXAS2, HOXAS3, HOXA11-AS, HOTAIRM1 and HOTTIP). We aimed to evaluate the prognostic role of HOXA-related lncRNAs in early stage non-small cell lung cancer (NSCLC).
100 early stage NSCLC patients resected in our center from June 2007 to November 2013 were studied. Patient characteristics: median age, 65 (32-84); 78% males; 74% stage I; 56% ADK; 23% received adjuvant treatment. With a mean follow-up of 28.7 months, 31% relapsed. As validation data set 200 NSCLC patients from TCGA Research Network were used (RNAseq data). Only stage I-II TCGA samples without prior malignancy or synchronous cancer that not received neoadjuvant treatment were included. Statistical analysis was performed using R and TANRIC.
HOTTIP and HOXA11AS impacted prognosis in our cohort of patients. HOTTIP was expressed in all samples and patients with high levels of HOTTIP had shorter TTR (78.3 vs 58 months; p = 0.048) and shorter OS (81.2 vs 61 months; p = 0.023). HOTTIP was overexpressed in SCC (p = 0.007) and in smokers (p = 0.018). HOXA11AS was expressed only in 9% of patients but the patients expressing HOXA11AS had shorter TTR (73.5 vs 32 months; p = 0.002). In the multivariate analysis HOXA11AS emerged as an independent prognostic marker for TTR (OR: 3.13, 95%CI: 1.3-7.3; p = 0.009), while HOTTIP (OR: 2.357, 95%CI: 1.1-5.2; p = 0.036) and age>65 (p = 0.022) for OS. In the validation data set HOXA11AS was validated as prognostic marker (p = 0.019). HOXA11AS expression correlated positively with development genes HOXA11, HOXA13, HOXA10, HOXA9, HOXA3, FOXD1, ZIC5 and miR-196b (HOXA cluster miRNA) and negatively with surfactant metabolism genes SFTPB and NAPSA or let-7a(p
HOXA11AS expression in early stage NSCLC patients is a high-risk relapse marker.
Clinical trial identification
Legal entity responsible for the study
University of Barcelona, Barcelona, Spain
All authors have declared no conflicts of interest.